Compounds with growth hormone releasing properties

ABSTRACT

Compounds of peptide mimetic nature having the general formula I formula I  
                 
 
     wherein a and b are independently 1 or 2, R 1  and R 2  are independently H or C 1-6 alkyl, G and J are independently, inter alia, aromats, and D and E are independently several different groups are growth hormone secretagogous with improved bioavailability.

FIELD OF INVENTION

[0001] The present invention relates to novel compounds, compositionscontaining them, and their use for treating medical disorders resultingfrom a deficiency in growth hormone.

BACKGROUND OF THE INVENTION

[0002] Growth hormone is a hormone which stimulates growth of alltissues capable of growing. In addition, growth hormone is known to havea number of effects on metabolic processes, e.g., stimulation of proteinsynthesis and free fatty acid mobilisation and to cause a switch inenergy metabolism from carbohydrate to fatty acid metabolism. Deficiencyin growth hormone can result in a number of severe medical disorders,e.g., dwarfism.

[0003] Growth hormone is released from the pituitary. The release isunder tight control of a number of hormones and neurotransmifters eitherdirectly or indirectly. Growth hormone release can be stimulated bygrowth hormone releasing hormone (GHRH) and inhibited by somatostatin.In both cases the hormones are released from the hypothalamus but theiraction is mediated primarily via specific receptors located in thepituitary. Other compounds which stimulate the release of growth hormonefrom the pituitary have also been described. For example arginine,L-3,4-dihydroxyphenylalanine (1-Dopa), glucagon, vasopressin, PACAP(pituitary adenylyl cyclase activating peptide), muscarinic receptoragonists and a synthethic hexapeptide, GHRP (growth hormone releasingpeptide) release endogenous growth hormone either by a direct effect onthe pituitary or by affecting the release of GHRH and/or somatostatinfrom the hypothalamus.

[0004] In disorders or conditions where increased levels of growthhormone is desired, the protein nature of growth hormone makes anythingbut parenteral administration non-viable. Furthermore, other directlyacting natural secretagogues, e.g., GHRH and PACAP, are longerpolypeptides for which reason parenteral administration is preferred.

[0005] The use of certain compounds for increasing the levels of growthhormone in mammals has previously been proposed, e.g. in EP 18 072, EP83 864, WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272,WO 91/18016, WO 92/01711, WO 93/04081, WO 9517422, WO 9517423 and WO9514666.

[0006] The composition of growth hormone releasing compounds isimportant for their growth hormone releasing potency as well as theirbioavailability. It is therefore the object of the present invention toprovide compounds of peptide mimetic nature with growth hormonereleasing properties which have improved properties relative to knowncompounds of this type.

SUMMARY OF THE INVENTION

[0007] In accordance with the present invention there is providedcompounds which act directly on the pituitary cells under normalexperimental conditions in vitro to release growth hormone therefrom.

[0008] These growth hormone releasing compounds can be utilized in vitroas unique research tools for understanding, inter alia, how growthhormone secretion is regulated at the pituitary level.

[0009] Moreover, the growth hormone releasing compounds of the presentinvention can also be administered in vivo to increase growth hormonerelease.

[0010] Accordingly, the present invention relates to a compound of thegeneral formula I

[0011] wherein

[0012] R¹ and R² are independently hydrogen, or

[0013] C₁₋₆alkyl optionally substituted with aryl;

[0014] a and b are independently 1 or 2;

[0015] G is hydrogen, —O—(CH₂)_(k)—R²⁷,

[0016] J is hydrogen, —O—(CH₂)_(l)R³²,

[0017] wherein

[0018] R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵ and R³⁶ independentlyare hydrogen, halogen, aryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;

[0019] k and l are independently 0, 1 or 2;

[0020] D is

[0021] wherein

[0022] R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently hydrogen orC₁₋₆-alkyl optionally substituted with halogen, amino, hydroxyl or aryl;

[0023] n, m and q are independently 0, 1, 2, or 3;

[0024] p is 0 or 1;

[0025] M is —CR¹¹═CR^(11a)—, aryl, —O—, or —S—;

[0026] R¹¹ and R^(11a) are independently hydrogen, or C₁₋₆-alkyloptionally substituted with aryl;

[0027] with the proviso that at least one of R³, R⁴, R⁵ and R⁶ isdifferent from hydrogen,

[0028] when E is

[0029] —CONR¹²R¹³, —(CH₂)_(v)—NR¹²SO₂R¹⁴, —(CH₂)_(v)—NR¹²COR¹³,—(CH₂)_(v)—OR^(13a), —CH₂)_(v)—OCOR¹³, —CH(R¹²)R¹³,—(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴, —(CH₂)_(v)-NR¹²—CO—NR¹³R¹⁴,

[0030] wherein

[0031] X is —N(R¹⁵)—, —O— or —S—,

[0032] V is —C(R¹⁶)═ or —N═,

[0033] Y is —C(R¹⁷)═ or —N═,

[0034] Z is —C(R¹⁸)═ or —N═,

[0035] R¹⁵ is hydrogen or C₁₋₆-alkyl optionally substituted with aryl,

[0036] R¹⁶, R¹⁷ and R¹⁸ independently are hydrogen, —COOR¹⁹, —CONR²⁰R²¹,—(CH₂)_(w)NR²⁰R²¹, —(CH₂)_(w)OR¹⁹, —(CH₂)_(w)R¹⁹ or halogen;

[0037] R¹², R¹³, R¹⁹, R²⁰ and R²¹ independently are hydrogen orC₁₋₆-alkyl optionally substituted with halogen, —CONR²²R²³, —N(R²²)R²³,—CF₃, hydroxyl, C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxyor aryl,

[0038] or R¹³ is

[0039] Q is —CH< or —N<,

[0040] K and L are independently —CH₂—, —CO—, —O—, —S—, —NR²⁶— or avalence bond, where R²⁶ is hydrogen or C₁₋₆-alkyl;

[0041] t and u are independently 0, 1, 2, 3 or 4;

[0042] R^(13a) is C₁₋₆ alkyl substituted with aryl;

[0043] R¹⁴ is C₁₋₆ alkyl;

[0044] R²² and R²³ are independently hydrogen or C₁₋₆-alkyl;

[0045] v and w are independently 0, 1, 2 or 3;

[0046] D is

R⁷—NH—(CR⁸R⁹)_(p)—(CH₂)_(m)—M—(CHR¹⁰)_(o)—(CH₂)_(n)—

[0047] wherein

[0048] R⁷, R⁸, R⁹and R¹⁰ are independently hydrogen or C₁₋₆ alkyloptionally substituted with halogen, amino, hydroxyl or aryl;

[0049] R⁷and R⁸ or R⁷and R⁹ or R⁸ and R⁹ optionally forming—(CH₂)_(i)—U—(CH₂)_(j)—, wherein i and j are independently are 1 or 2and U is —O—, —S— or a valence bond;

[0050] n and m are independently 0, 1, 2, or 3;

[0051] o and p are independently 0 or 1;

[0052] M is —CR¹¹═CR^(11a)—, aryl, —O—, or —S—;

[0053] R¹¹ and R^(11a) are independently hydrogen, or C₁₋₆-alkyloptionally substituted with aryl,

[0054] when E is

[0055] —CONR¹²R¹³, —(CH₂)_(v)—NR¹²SO₂R¹⁴, —(CH₂)_(v)—NR¹²COR¹³,—(CH₂)_(v)—OR^(13a), —CH₂)_(v)—OCOR¹³, —CH(R¹²)R¹³,—(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴ or —(CH₂)_(v)—NR¹²—CO—NR¹³R¹⁴,

[0056] wherein

[0057] R¹² and R¹³ independently are hydrogen or

[0058] C₁₋₆-alkyl optionally substituted with halogen, —CONR²²R²³,—N(R²²)R²³, —CF₃, hydroxyl, C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyloxy or aryl;

[0059] or R¹³ is

[0060] Q is —CH< or —N<,

[0061] K and L are independently —CH₂—, —CO—, —O—, —S—, —NR²⁶— or avalence bond, where R²⁶ is hydrogen or C₁₋₆ alkyl;

[0062] t and u are independently 0, 1, 2, 3 or 4;

[0063] R^(13a) is C₁₋₆ alkyl substituted with aryl;

[0064] R¹⁴ is C₁₋₆ alkyl;

[0065] R²² and R²³ are independently hydrogen or C₁₋₆ alkyl;

[0066] v and w are independently 0, 1, 2 or 3;

[0067] or a pharmaceutically acceptable salt thereof, and the compoundsof formula I comprise any optical isomers thereof, in the form ofseparated, pure or partially purified optical isomers or racemicmixtures thereof.

[0068] In the compound of the above formula I D is preferably

[0069] 3-(1-aminoethyl)phenyl, 4-amino-4-ethylhex-1-enyl,(1E)-2-(azetidin-3-yl)ethenyl, piperidin-4-ylidenyl,2-methylpiperidin-4-yl, 2-methylpiperidin-3-yl, 2-methylpiperidin-5-yl,(1,2,3,4-tetrahydroisoquinolin-1-yl)methyl, 4-aminocyclohexyl,2-piperidylmethoxymethyl,

[0070] 4-piperidyloxymethyl, 2-(2-amino-2-methylpropyl)cyclopropyl,(((2R)-pyrrolidin-2-yl)methoxy)methyl,(1E)-4-amino-1-benzyl-4-methylpent-1-enyl,(1E)-4-amino-4-methylpent-1-enyl, (2-amino-2-methylpropoxy)methyl,(2S)-(2-pyrrolidinyl)methoxymethyl, (2R)-(2-pyrrolidinyl)methoxymethyl,(1E)-4-amino-2,4-dimethylpent-1-enyl,(1E)-4-methyl-4-(methylamino)pent-1-enyl,(1Z)-4-amino-4-methylpent-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(2-aminobutoxy)methyl, 3-(1-aminoethyl)phenyl, 3-aminomethylphenyl,3-(1-amino-1-methylethyl)phenyl, 2-(1-amino cyclopropyl)ethenyl,3-(1-aminocyclobutyl)-1-propenyl, 3-(1-aminocyclopropyl)-1-propenyl or2-(1-amino cyclobutyl)ethenyl.

[0071] In the compound of the above formula I E is preferablymethylcarbamoyl, ethylcarbamoyl, N,N-dimethylcarbamoyl,

[0072] 2-methoxyethylcarbamoyl, (2S)-2-hydroxypropylcarbamoyl,(2R)-2-hydroxypropylcarbamoyl, (cyclopropylmethyl)carbamoyl,(2-(acetoxy)-2-methylpropyl)carbamoyl, phenylethylcarbamoyl,4-pyridylcarbamoyl, (3-acetoxypropyl)carbamoyl,(3-hydroxypropyl)carbamoyl, methylsulfonylaminomethyl,((tetrahydrofuran-2-yl)methyl)carbamoyl, 3-cyclopropylthioureido,N-methyl-N-(methylsulfonylamino)methyl, (2,2,2-trifluoroethyl)carbamoyl,cyclopropylcarbamoyl, ((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl,3-methyl-1,2,4-oxadiazol-5-yl, methylsulfonylaminomethyl,2,2-dimethyl-3-hydroxypropylcarbamoyl,2-(1-methylpyrrolidine-2-yl)ethylcarbamoyl,N-methyl-N-(3-(dimethylamino)propyl)carbamoyl, N-(N,N-dimethylcarbamoyl)-N-methylcarbamoyl, N-(carbamoylmethyl)carbamoyl or3-cyclopropylthioureido.

[0073] In the compound of the above formula I G is preferably

[0074] 2-naphthyl, 1-naphthyl, 2-benzyloxy, biphenyl-4-yl or3-benzo[b]thiophenyl, 4-methoxyphenyl, 2,3,4,5,6-pentafluorophenyl.

[0075] In the compound of the above formula I J is preferably

[0076] phenyl, 2-fluorophenyl, 4-fluorophenyl, 4-iodophenyl,3,4-difluorophenyl 2-thienyl, 4-methoxyphenyl,2,3,4,5,6-pentafluorophenyl, 2-naphthyl or 1-naphthyl.

[0077] In the compound of the above formula I R¹ is preferably

[0078] hydrogen, methyl or ethyl.

[0079] More preferably R¹ is hydrogen, or methyl.

[0080] In the compound of the above formula I R² is preferably hydrogen,methyl or ethyl.

[0081] In the compound of the above formula I a is preferably 1.

[0082] In the compound of the above formula I b is preferably 1.

[0083] Preferred compounds of the invention are:

[0084] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0085] (2E)-3-(3-Azetidinyl)acrylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0086] 2-(Piperidin-4-ylidene)acetic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0087] 2-(2-Amino-2methylpropyl)cyclopropanecarboxylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2(2-naphthyl)ethyl)amide:

[0088] 2-(2-Amino-2-methylpropoxy)acetic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0089] 2-Methylpiperidine-4-carboxylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0090] 2-Methylpiperidine-3-carboxylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0091] 2-Methylpiperidine-5-carboxylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2naphthyl)ethyl)amide:

[0092] 2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0093] 4-Aminocyclohexanecarboxylic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0094] (2E)-5-Amino -5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(benzylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0095] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(phenethylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0096] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-{N-[(1R)-1-(acetylaminomethyl)-2-phenylethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide:

[0097] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-methyl-N-[(1R)-1-(methylsulfonylaminomethyl)-2-phenylethyl]carbamoyl}-2-(2-naphthyl)ethyl)amide:

[0098] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-((cyclopropyl-methyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0099] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(N-(2-methoxy-ethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0100] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((N-tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0101] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(N-(2S)-2hydroxy-methylamide:

[0102] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(N-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0103] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-{N-[(1R)-1-((2,5-dioxopyrrolidine-1-yl)methyl)-2-phenylethyll-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide:

[0104](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methyl-amino-N-methyl-3(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide:

[0105] (2E)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((2-tetra-hydrofuranyl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0106] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)-N-methylamide:

[0107](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-((R)-1-(cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)-propionamide:

[0108](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)methylamino)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide:

[0109] (2E)-5-Amino-5-methylhex-2-enoic AcidN-(1R)-1-(N-((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0110](2R)-2-(N-((2-Amino-2methylpropoxy)acetyl)N-methylamino)-N-((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide:

[0111] (2E)-5-Amino-5-methylhex-2-enoic Acid((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide:

[0112] (2E)-5-Amino-3, 5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0113]2-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1 dimethylethyl acetate:

[0114] (2E)-5-Amino-2-benzyl-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0115] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(1-naphthyl)ethyl)amide:

[0116](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide:

[0117] (2E)-5-Amino-5-methylhex-2-enoic Acid N-((iR)-2-(benzo[b]thiophen-3-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)N-methylamide:

[0118](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methyl-amino)-3-(benzo[b]thio-phen-3-yl)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide:

[0119] (2E)-5Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1(((tetrahydrofuran-2-yl)-methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)amide:

[0120]3-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate:

[0121] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(3-hydroxypropyl-carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-amide:

[0122] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0123]N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-{[(2-piperidinyl)methoxy]acetyl}amino)-3-(2-naphthyl)propionamide:

[0124] 4-Aminocyclohexanecarboxylic AcidN-methyl-N-((1R)-1-[N-methyl-N-{(1R)-1-(methylcarbamoyl)-2-phenylethyl}carbamoyl]-2-(2-naphthyl)ethyl)amide:

[0125](2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N[{piperidin-4-yloxy}acetyl]amino)-3-(2naphthyl)propionamide:

[0126] 2-Methyl-piperidine-carboxylic AcidN{1-[N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2-naphthyl)ethyl}amide:

[0127](2R)-2-(N-((2R)-2-(N-((2E)-5((2R)-2-Hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide;

[0128] (2E)-5-Amino-N-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-5-methyl-N-methylhex-2-enamide;

[0129] 3-(1-Aminoethyl)benzoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0130] 5-Amino-5-methyl-hex-2-enoic Acid((1R)-1-(((1R)-1-((2R)-2-hydroxypropylcarbamoyl)-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide:

[0131] (4-(1-Aminocyclobutyl)but-2-enoic Acid((1R)-1-(((1R)-1-(1-methylcarbamoyl-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide:

[0132] 5-Amino-5-methyl-hex-2-enoic Acid((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(2-thienyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide.

[0133](2R)-2-(N-[(2R)-2-(N-[(2-Aminobutoxy)acetyl]-N-methylamino)-3-(2-naphthyl)propionyl]-N-methylamino)-N-methyl-3-phenylpropionamide:

[0134](2R)-N-Methyl-2-(N-methyl-N-((2R)-2-(N-methyl-N-((((2S)-pyrrolidin-2-yl)methoxy)acetyl)amino)-3-(2-naphthyl)propionyl)amino)-3-phenylpropionamide

[0135]3-((2R)-2-(N-((2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate

[0136] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)2-(2-naphthyl)ethyl)-N-methylamide:

[0137] (2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-[{piperidine-4yloxy}acetyl]amino)-3-(2-naphthyl)propionamide

[0138]N-Methyl-N-((1R)-1-methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-{[(2-piperidinyl)methoxy]acetyl}amino)-3-(2-naphthyl)propinamide

[0139] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)amide:

[0140] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0141] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0142] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl)-2-(1-naphthyl)ethyl)amide:

[0143] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl)-2-phenylethyl)amide:

[0144] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-(1-naphthyl)ethyl)amide:

[0145] (2E)-5-Amino-5methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0146] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2,3,4,5,6-pentafluorophenyl)ethyl)amide:

[0147] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0148] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-(1-naphthyl)ethyl)amide:

[0149] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-(4-methoxyphenyl)ethyl)amide:

[0150] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0151] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0152] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2,3,4,5,6-pentafluorophenyl)ethyl)amide:

[0153] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0154] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide

[0155] (2E)-5-Methyl-5-methylaminohex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide

[0156] (2E)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[0157] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-(2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)amide

[0158] 5-Amino-3,5-dimethylhex-2-enoic AcidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide.

[0159] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[0160] (2E)-5-Methyl-5-methylaminohex-2-enoic AcidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[0161] (2E) 5-Methyl-5-amino-5-methylhex-2-enoicacid-N-methyl-N-((1R)-2-(N-methyl-N-((1R)-(methylcarbamoyl)-2-(thien-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[0162] 5-methylamino-hex-2-enoic Acid((1R)-1-(((1R)-2-(3,4-difluorophenyl)-1-methylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide

[0163] 5-methylamino-hex-2-enoic Acid((1R)-1-(((1R)-2-phenyl-1-ethylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide

[0164] 5-Amino-5-methyl-hex-2-enoic Acid((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(3,4-difluorophenyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide.

[0165] 5-Amino-5-methyl-hex-2-enoic Acid(1-{[2-(2fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2-naphthyl)ethyl)methylamide.

[0166] (2Z)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[0167](2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-3-(2-naphthyl)propionamide

[0168](2R)-2-(N-[}2-Amino-2-methylpropoxy}acetyl]-N-methylamino)-N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)propionamide:

[0169](2E)-5-Amino-5-methyl-N-methyl-N((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,and its acetate salt;

[0170] (2E)-5-Amino-5-methylhex-2-enoic acid

[0171]N-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;

[0172] (2E)-4-(1-Aminocyclobutyl)but-2-enoic acidN-((1R)-1-(N-((1R)-2-(3,4-difluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;

[0173] (2E)-4-(1-Aminocyclobutyl)but-2-enoic acidN-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)N-methylamide;

[0174] (2E)-4-(1-Aminocyclobutyl)-but-2-enoic acidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide;

[0175]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2(2thienyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0176]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0177](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;

[0178](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;

[0179](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;

[0180]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;

[0181]3-(1-Aminomethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;

[0182](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0183](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0184](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0185] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;

[0186]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0187]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0188](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;

[0189](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;

[0190](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;

[0191] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide;

[0192]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0193]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0194](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0195](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0196](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0197] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide;

[0198]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0199]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0200](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;

[0201](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;

[0202](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;

[0203]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;

[0204]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;

[0205](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0206](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0207](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0208]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0209]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0210](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;

[0211](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;

[0212](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;

[0213]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0214]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0215](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0216]

[0217](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0218](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0219] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide;

[0220]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;

[0221]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;

[0222](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0223](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0224](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0225] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;

[0226]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0227]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0228](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;

[0229](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;

[0230](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;

[0231]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0232]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0233](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;

[0234](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;

[0235](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;

[0236]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0237]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;

[0238](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide;

[0239](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)-propionamide;

[0240](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide;

[0241] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(2-naphthyl)-ethyl)amide;

[0242]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;

[0243]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;

[0244](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0245](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;

[0246] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;

[0247]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0248]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;

[0249](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;

[0250](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;

[0251](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;

[0252] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide;

[0253]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(biphen-4-yl)ethyl)benzamide;

[0254]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;

[0255](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide;

[0256](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide;or

[0257](2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide.

[0258] It is believed that compounds of formula I exhibit an improvedresistance to proteolytic degradation by enzymes because they arenon-natural, in particular because the natural amide bonds are replacedby non-natural amide bond mimetics. The increased resistance toproteolytic degradation combined with the reduced size of the compoundsof the invention in comparison with known hormone releasing peptides isexpected to improve their bioavailability compared to that of thepeptides suggested in the prior literature.

[0259] In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

[0260] The C₁₋₆-alkyl groups specified above are intended to includethose alkyl groups of the designated length in either a linear orbranched or cyclic configuration, Examples of linear alkyl groups aremethyl, ethyl, propyl, butyl, pentyl and hexyl. Examples of branchedalkyl groups are isopropyl, sec-butyl, tert-butyl, isopentyl, andisohexyl. Examples of cyclic alkyl are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

[0261] Especially preferred C₁₋₆-alkyl groups are the C₁₋₃-alkyl groups.Preferred C₁₋₃-alkyl groups are methyl, ethyl, isopropyl andcyclopropyl.

[0262] The C₁₋₆-alkoxy groups specified above are intended to includethose alkoxy groups of the designated length in either a linear orbranched or cyclic configuration. Examples of linear alkoxy groups aremethoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples ofbranched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy andisohexoxy. Example of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy,cyclopentyloxy and cyclohexyloxy.

[0263] Especially preferred C₁₋₆-alkoxy groups are the C₁₋₃-alkoxygroups. Preferred C₁₋₃-alkoxy groups are methoxy, ethoxy, isopropoxy andcyclopropoxy.

[0264] In the present context, the term C₁₋₆-alkoxycarbonyl is intendedto include the above defined C₁₋₆-alkoxy groups attached to a carbonylmoiety.

[0265] In the present context, the term C₁₋₆-alkoxycarbonyloxy isintended to include the above defined C₁₋₆-alkoxy groups attached to acarbonyloxy moiety.

[0266] In the present context, the term “aryl” is intended to includearomatic rings, such as carboxyclic and heterocyclic aromatic ringsselected from the group consisting of phenyl, naphthyl, pyridyl,tetrazolyl, thiazolyl, imidazolyl, indolyl, quinolinyl, pyrimidinyl,thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, furanyl oroxadiazolyl optionally substituted with halogen, amino, hydroxy,C₁₋₆-alkyl or C₁₋₆-alkoxy. Aryl is preferably phenyl, thienyl,imidazolyl, pyridyl, indolyl, oxadiazole or naphthyl optionallysubstituted with halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy.

[0267] The term “halogen” includes Cl, F, Br and I.

[0268] The compounds of the present invention may have one or moreasymmetric centres and it is intended that stereoisomers, as separated,pure or partially purified stereoisomers or racemic mixtures thereof areincluded in the scope of the invention.

[0269] Pharmaceutically acceptable acid addition salts of compounds offormula I include those prepared by allowing the compound to react withan inorganic or organic acid such as hydrochloric, hydrobromic,sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric,glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric,toluenesulfonic, trifluoroacetic, sulfamic or fumaric acid.

[0270] In another aspect, the present invention relates to apharmaceutical composition comprising, as an active ingredient, acompound of the general formula I or a pharmaceutically acceptable saltthereof together with a pharmaceutically acceptable carrier or diluent.

[0271] Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington's Pharmaceutical Sciences, 1985. The compositions mayappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

[0272] The pharmaceutical carrier or diluent employed may be aconventional solid or liquid carrier. Examples of solid carriers arelactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin,acacia, magnesium stearate, stearic acid or lower alkyl ethers ofcellulose. Examples of liquid carriers are syrup, peanut oil, olive oil,phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.

[0273] Similarly, the carrier or diluent may include any sustainedrelease material known in the art, such as glyceryl monostearate orglyceryl distearate, alone or mixed with a wax.

[0274] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. Theamount of solid carrier will vary widely but will usually be from about25 mg to about 1 g. If a liquid carrier is used, the preparation may bein the form of a syrup, emulsion, soft gelatin capsule or sterileinjectable liquid such as an aqueous or non-aqueous liquid suspension orsolution.

[0275] A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose,microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mgMagnesium stearate Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx.0.9 mg

[0276] For nasal administration, the preparation may contain a compoundof formula I dissolved or suspended in a liquid carrier, in particularan aqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

[0277] Generally, the compounds of the present invention are dispensedin unit dosage form comprising 50-200 mg of active ingredient togetherwith a pharmaceutically acceptable carrier per unit dosage.

[0278] The dosage of the compounds according to this invention issuitably 0.1-500 mg/day, e.g. from about 5 to about 50 mg, such as about10 mg per dose, when administered to patients, e.g. humans, as a drug.

[0279] The compounds of the invention possess interestingpharmacological properties, and it has been demonstrated that compoundsof the general formula I possess the ability to release endogenousgrowth hormone in vivo. The compounds may therefore be used in thetreatment of conditions which require increased plasma growth hormonelevels such as in growth hormone deficient humans or in elderly patientsor livestock.

[0280] Thus, in a particular aspect, the present invention relates to apharmaceutical composition for stimulating the release of growth hormonefrom the pituitary, the composition comprising, as an active ingredient,a compound of the general formula I or a pharmaceutically acceptablesalt thereof together with a pharmaceutically acceptable carrier ordiluent.

[0281] In a further aspect, the present invention relates to a method ofstimulating the release of growth hormone from the pituitary, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the general formula I or a pharmaceuticallyacceptable salt thereof.

[0282] In a still further aspect, the present invention relates to theuse of a compound of the general formula I or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament forstimulating the release of growth hormone from the pituitary.

[0283] To those skilled in the art, it is well known that the currentand potential uses of growth hormone in humans are varied andmultitudinous. Thus, compounds of formula I can be administered forpurposes stimulating release of growth hormone from the pituitary andwould then have similar effects or uses as growth hormone itself. Theuses of growth hormone may be summarized as follows: stimulation ofgrowth hormone release in the elderly; prevention of catabolic sideeffects of glucocorticoids, prevention and treatment of osteoporosis,stimulation of the immune system, acceleration of wound healing,accelerating borte fracture repair, treatment of growth retardation,treating renal failure or insufficiency resulting from growthretardation, treatment of physiological short stature including growthhormone deficient children and short stature associated with chronicillness, treatment of obesity and growth retardation associated withobesity, treating growth retardation associated with the Prader-Willisyndrome and Tumer's syndrome; accelerating the recovery and reducinghospitalization of burn patients; treatment of intrauterine growthretardation, skeletal dysplasia, hypercortisolism and Cushing'ssyndrome; induction of pulsatile growth hormone release; replacement ofgrowth hormone in stressed patients, treatment ofosteochondrodysplasias, Noonan's syndrome, schizophrenia, depressions,Alzheimer's disease, delayed wound healing and psychosocial deprivation,treatment of pulmonary dysfunction and ventilator dependency,attenuation of protein catabolic responses after major surgery, reducingcachexia and protein loss due to chronic illness such as cancer or AIDS;treatment of hyperinsulinemia including nesidioblastosis, adjuvanttreatment for ovulation induction; to stimulate thymic development andprevent the age-related decline of thymic function, treatment ofimmunosuppressed patients, improvement in muscle strength, mobility,maintenance of skin thickness, metabolic homeostasis, renal homeostasisin the frail elderly, stimulation of osteoblasts, bone remodelling andcartilage growth, stimulation of the immune system in companion animalsand treatment of disorder of aging in companion animals, growth promoterin livestock and stimulation of wool growth in sheep.

[0284] For the above indications the dosage will vary depending on thecompound of formula I employed, on the mode of administration and on thetherapy desired. However, generally dosage levels between 0.0001 and 100mg/kg body weight daily are administered to patients and animals toobtain effective release of endogenous growth hormone. Usually, dosageforms suitable for oral, nasal, pulmonal or transdermal administrationcomprise from about 0.0001 mg to about 100 mg, preferably from about0.001 mg to about 50 mg of the compounds of formula I admixed with apharmaceutically acceptable carrier or diluent.

[0285] The compounds of formula I may be administered inpharmaceutically acceptable acid addition salt form or, whereappropriate, as a alkali metal or alkaline earth metal or loweralkylammonium salt. Such salt forms are believed to exhibitapproximately the same order of activity as the free base forms.

[0286] Optionally, the pharmaceutical composition of the invention maycomprise a compound of formula I combined with one or more compoundsexhibiting a different activity, e.g., an antibiotic or otherpharmacologically active material.

[0287] The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral, theoral route being preferred.

[0288] Apart from the pharmaceutical use of the compounds of formula I,they may be useful in vitro tools for investigating the regulation ofgrowth hormone release.

[0289] Compounds of formula I may also be useful in vivo tools forevaluating the growth hormone releasing capability of the pituitary. Forexample, serum samples taken before and after administration of thesecompounds to humans can be assayed for growth hormone. Comparison of thegrowth hormone in each serum sample would directly determine the abilityof the patients pituitary to release growth hormone.

[0290] Compounds of formula I may be administered to commerciallyimportant animals to increase their rate and extent of growth, and toincrease milk production.

[0291] A further use of growth hormone secretagogue compounds of formulaI is in combination with other secretagogues such as GHRP (2 or 6), GHRHand its analogues, growth hormone and its analogues or somatomedinsincluding IGF-1 and IGF-2.

[0292] Pharmacological Methods

[0293] Compounds of formula I may be evaluated in vitro for theirefficary and potency to is release growth hormone in rat pituitaryprimary cultures.

[0294] The isolation of rat pituitary cells is a modification of O.Sartor et al., Endocrinology 116, 1985, pp. 952-957. Male albinoSprague-Dawley rats (250+/−25 grams) were purchased from Møllegaard,Lille Skensved, Denmark. The rats were housed in group cages (fouranimals/cage) and placed in rooms with 12 hour light cycle. The roomtemperature varied from 19-24° C. and the humidity from 30-60%.

[0295] The rats were decapitated and the pituitaries dissected. Theneurointermediate lobes were removed and the remaining tissue wasimmediately placed in icecold isolation buffer (Gey's medium (Gibco041-04030) supplemented with 0.25% D-glucose, 2% non-essential aminoacids (Gibco 043-01140) and 1% bovine serum albumine (BSA) (SigmaAA503)). The tissue was cut into small pieces and transferred toisolation buffer supplemented with 3.8 mg/ml of trypsin (Worthington#3707 TRL-3) and 330 mg/ml of DNase, (Sigma D4527). This mixture wasincubated at 70 rotations/min for 35 min at 37° C. in a 95/5% atmosphereof O₂/CO₂. The tissue was then washed three times in the above buffer.Using a standard pasteur pipet, the tissue was then aspirated intosingle cells. After dispersion, cells were filtered through a nylonfilter (160 mm) to remove undigested tissue. The cell suspension waswashed 3 times with isolation buffer supplemented with trypsin inhibitor(0.75 mg/ml, Worthington #2829) and finally resuspended in culturemedium; DMEM (Gibco 041-01965) supplemented with 25 mM HEPES (SigmaH-3375),4 mM glutamine (Gibco 043-05030H), 0.075% sodium bicarbonate(Sigma S-8875), 0.1% non-essential amino acid, 2.5% fetal calf serum(FCS, Gibco 011-06290), 3% horse'serum (Gibco 034-06050), 10% fresh ratserum, 1 nM T₃ (Sigma T-2752) and 40 mg/L dexamethasone (Sigma D4902) pH7.3, to a density of 2×10⁵ cells/ml. The cells were seeded intomicrotiter plates (Nunc, Denmark), 200-ml/well, and cultured for 3 daysat 37° C. and 8% CO₂.

[0296] Compound Testing

[0297] After culturing, the cells were washed twice with stimulationbuffer (Hanks Balanced Salt Solution (Gibco 041-04020) supplemented with1% BSA (Sigma AA503), 0.25% D-glucose (Sigma G-5250) and 25 mM HEPES(Sigma H-3375) pH 7.3) and preincubated for 1 hour at 37° C. The bufferwas exchanged with 90 ml stimulation buffer (37° C.). Ten ml testcompound solution was added and the plates were incubated for 15 min at37° C. and 5% CO₂. The medium was decanted and analyzed for GH contentin an rGH SPA test system.

[0298] All compounds were tested in doses ranging from 10 pM to 100 mM.A dose-response relation was constructed using the Hill equation (Fig P,Biosoft). The efficacy (maximal GH released, E_(maz)) was expressed in %of the E_(max) of GHRP-6. The potency (EC₅₀) was determined as theconcentration inducing half maximal stimulation of the GH release.

[0299] Compounds of formula I may be evaluated for their metabolicstability.

[0300] Compounds were dissolved at a concentration of 1 mg/ml in water.25 ml of this solution is added to 175 ml of the respectiveenzyme-solution (resulting in an enzyme:substrate ratio (w/w) ofapproximately 1:5). The solution is left at 37° C. overnight. 10 ml ofthe various degradation solutions is analyzed against a correspondingzero-sample using flow injection electrospray mass spectrometry (ESMS)with selected ion monitoring of the molecular ion. If the signal hasdecreased more than 20% compared to the zero-sample, the remainder ofthe solution is analyzed by HPLC and mass spectrometry in order toidentify the extent and site(s) of degradation precisely.

[0301] Several standard peptides (ACTH 4-10, Angiotensin 1-14 andGlucagon) have been included in the stability tests in order to verifythe ability of the various solutions to degrade peptides.

[0302] Standard peptides (angiotensin 1-14, ACTH 4-10 and glucagon) werepurchased from Sigma, Mo., USA)

[0303] Enzymes (trypsin, chymotrypsin, elastase aminopeptidase M andcarboxypeptidase Y and B) were all purchased from Boehringer MannheimGmbH (Mannheim, Germany)

[0304] Pancreatic enzyme mix: trypsin, chymotrypsin and elastase in 100mM ammoniumbicarbonate pH 8.0 (all concentrations 0.025 mg/ml).

[0305] Carboxypeptidase mix: carboxypeptidase Y and B in 50 mMammoniumacetate pH 4.5 (all concentrations 0.025 mg/ml).

[0306] Aminopeptidase M solution: aminopeptidase M (0.025 mg/ml) in 100mM ammoniumbicarbonate pH 8.0.

[0307] Mass spectrometric analysis was performed using two differentmass spectrometers. A Sciex API III triple quadrupole LC-MS instrument(Sciex instruments, Thornhill, Ontario) equipped with an electrosprayion-source and a Bio-Ion 20 time-of-flight Plasma Desorption instrument(Bio-Ion Nordic AB, Uppsala, Sweden).

[0308] Quantification of the compounds (before and after degradation)was done on the API III instrument using single ion monitoring of themolecular ion in question with flow injection of the analyte. The liquidflow (MeOH:water 1:1) of 100 ml/min was controlled by an ABI 140B HPLCunit (Perkin-Elmer Applied Biosystems Divisions, Foster City, Calif.).The instrument parameters were set to standard operation conditions, andSIM monitoring was performed using the most intense molecular ion (inmost cases this corresponded to the doubly charged molecular ion).

[0309] Identification of degradation products furthermore involved theuse of plasma desorption mass spectrometry (PDMS) with sampleapplication on nitrocellulose coated targets and standard instrumentalsettings. The accuracy of the hereby determined masses is generallybetter than 0.1%.

[0310] Separation and isolation of degradation products was done using aHY-TACH C-18 reverse phase 4.6×105 mm HPLC column (Hewlett-PackardCompany, Palo Alto, Calif.) with a standard acetonitril:TFA separationgradient. The HPLC system used was HP1090M (Hewlett-Packard Company,Palo (Alto, Calif.). Carboxy- Pan. Peptide MW/SIM peptidase enzymederivative ion (amu) mix mix Standards ACTH 4-10 1124.5/562.8  + −Glucagon  3483/871.8 − − Insulin (B23-29) 859.1/430.6 Angiotensin 1-141760.1/881.0  − − GHRP-2 817.4/409.6 − − GHRP-6 872.6/437.4 − −

[0311] Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

[0312] The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

[0313] The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry(MS). NMR shifts (d) are given in parts per million (ppm) and onlyselected peaks are given. mp is melting point and is given in ° C.Column chromatography was carried out using the technique described byW.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel60 (Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se. Abbrevations: TLC: thin layer chromatography DMSO:dimethylsulfoxide CDCl₃: deutorated chloroform DMF:N,N-dimethylformamide min: minutes h: hours

[0314] HPLC-Analysis:

[0315] Method B1.

[0316] The RP-HPLC analysis was performed using UV detection at 214 nmand a Vydac 218TP54 4.6 mm×250 mm 5 m C-18 silica column (TheSeperations Group, Hesperia), which was eluted at 1 ml/minute. Twosolvent systems were used: Solvent system I: 0.1% Trifluoroacetic acidin acetonitrile. Solvent system II: 0.1% rifluoroacetic acid in water.

[0317] The column was equilibrated with a mixture composed of 5% ofsolvent system I and 95% of solvent system II. After injection of thesample a gradient of 5% to 60% of solvent system I in solvent system IIwas run over 50 minutes. The gradient was then extended to 100% ofsolvent system I over 15 minutes followed by isocratic elution with 100%of this system for 5 minutes.

[0318] Method A1.

[0319] The RP-analysis was performed using UV detections at 214, 254,276, and 301 nm on a Vydac 218TP54 4.6 mm×250 mm 5 m C-18 silica column(The Seperations Group, Hesperia), which was eluted at 1 mumin at 42° C.The column was equilibrated with 5% acetonitrile in a buffer consistingof 0.1 M ammonium sulfate, which was adjusted to pH 2.5 with 4M sulfuricacid. after injection the sample was eluted by a gradient of 5% to 60%acetonitrile in the same buffer during 50 min.

Example 1

[0320] (2E) 5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amidehydrochloride:

[0321] 3-Hydroxy-1,1-dimethylpropylcarbamic Acid Tert-butyl Ester:

[0322] Step A:

[0323] At 0° C., ethyl chloroformate (1.10 mL, 11.5 mmol) was givendropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoicacid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) intetrahydrofuran (10 mL). The solution was stirred for 40 min at 0° C.The formed precipitate was filtered off and washed with tetrahydrofuran(20 mL). The liquid was immediately cooled to 0° C. A 2M solution oflithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was addeddropwise. The solution was stirred at 0° C. for 2 h, and then warmed toroom temperature. over a period of 4 h. It was cooled to 0° C. Methanol(5 mL) was added carefully. 1 N Hydrochloric acid (100 mL) was added.The solution was extracted with ethyl acetate (2×100 mL, 3×50 mL). Thecombined organic layers were washed with saturated sodium hydrogencarbonate solution (100 mL) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was chromatographed onsilica (110 g) with ethyl acetatelheptane 1:2 to give 1.84 g of3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester.

[0324]¹H-NMR (CDCl₃): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94(br, 1H); 3.75 (q, 2H); 4.98 (br, 1H).

[0325] 3-(tert-Butoxycarbonylamino)-3-methylbutanal:

[0326] Step B:

[0327] DMSO (1.22 mL, 17.2 mmol) was added to a solution of oxalylchloride (1.1 mL, 12.9 mmol) at −78° C. in dichloromethane (15 mL). Themixture was stirred for 15 min at −78° C. A solution of3-hydroxy-1,₁-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6mmol) in dichloromethane (10 mL) was added dropwise over a period of 15min. The solution was stirred at -78° C. for another 15 min.

[0328] Triethylamine (6.0 mL, 43 mmol) was added. The solution wasstirred at −78° C. for 5 min and then warmed to room temperature. Thesolution was diluted with dichloromethane (100 mL) and extracted with 1Nhydrochloric acid (100 mL). The aqueous phase was extracted withdichloromethane (50 mL). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 mL) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by column chromatography on silica (140 g) with ethylacetate/heptane (1:3) to give 1.10 g of3-(tert-butoxycarbonylamino)-3-methylbutanal.

[0329] MHz-¹H-NMR (CDCl₃): d 1.39 (s, 6H); 1.45 (s, 9H); 2.85 (d, 2H);4.73 (br. 1H); 9.80 (t, 1H).

[0330] Ethyl (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoate:

[0331] Step C:

[0332] Triethylphoshonoacetate (1.96 mL, 9.8 mmol) was dissolved intetrahydrofuran (30 mL). Potassium tert-butoxide (1.10 g, 9.8 mmol) wasadded. The solution was stirred for 40 min at room temperature. Asolution of 3-(tert-butoxycarbonylamino)-3-methylbutanal (1.10 g, 5.5mmol) in Tetrahydrofuran (6 mL) was added. The solution was stirred atroom temperature. for 75 min. It was diluted with ethyl acetate (100 mL)and 1N hydrochloric acid (100 mL). The phases were separated. Theaqueous phase was extracted with ethyl acetate (2×50 mL). The combinedorganic phases were washed with saturated sodium hydrogen carbonatesolution (60 mL) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by columnchromatography on silica (90 g) with ethyl acetate/hepatane (1:4) togive 1.27 g of ethyl(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate.

[0333]¹H-NMR (CDCl₃): d 1.30 (s, 6H); 1.30 (t, 3H); 1.46 (s, 9H); 2.62(d, 2H); 4.27 (q, 2H); 4.42 (br, 1H); 5.88 (d, 1H); 6.94 (td, 1H).

[0334] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic Acid:

[0335] Step D:

[0336] Ethyl (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoate(1.233 g, 4.54 mmol) was dissolved in dioxane (20 mL). Lithium hydroxide(0.120 g, 5.00 mmol) was added as a solid. Water (10 mL) was added,until a clear solution was reached. The solution was stirred 16 h atroom temperature. The solution was diluted with water (70 mL) and wasextracted with tert-butyl methyl ether (2×100 mL). The aqueous phase wasacidified with 1 N sodium hydrogensulfate solution is (pH=1) and wasextracted with tert-butylmethylether (3×70 mL). The organic phases werecombined and dried over magnesium sulfate. The solvent was removed invacuo to give 1.05 g of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid. The crudeproduct was used for further syntheses.

[0337]¹H-NMR (DMSO d,): d 1.15 (s, 6H); 1.35 (s, 9H); 2.53 (d, 2H); 5.75(d, 1H); 6.57 (br, 1H); 6.75 (td, 1H); 12.15 (s, 1H).

[0338] N-Methyl-N-((R)-1-(methylcarbamoyl)-2-phenylethyl)carbamic AcidTert-Butyl Ester:

[0339] Step E:

[0340] N-Tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.22 g, 4.4mmol), 1-hydroxybenzotriazole hydrate(0.59 g, 4.4 mmol) and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimid hydrochloride (0.88 g, 4.6mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred for 30min. Methylamine (0.51 g of a 40% solution in methanol, 6.6 mmol) wasadded and the mixture was stirred overnight. Methylene chloride (80 mL)and water (100 mL) were added and the phases were separated. The organicphase was washed with sodium hydroxide (20 mL, 1N), sodiumhydrogensulfate (50 mL, 10%) and water (50 mL). The organic phase wasdried (magnesium sulfate) and the solvent removed in vacuo to afford1.39 g of N-methyl-N-((R)1-(methylcarbamoyl)-2-phenylethyl)carbamic acidtert-butyl ester.

[0341]¹H-NMR (CDCl₃): d 1.25, 1.35 (two s (br), 9H); 2.73-2.94 (m, 7H);3.30-3.50 (m, I H); 4.68, 4.90 (two m, 1H); 5.90, 6.12 (two s (br); 1H);7.12-7.25 (m, 5H).

[0342] (R)-N-Methyl-2-methylamino-3-phenylpropionamide:

[0343] Step F:

[0344] N-Methyl-N-((R)-1-(methylcarbamoyl)-2-phenylethyl)carbamic acidtert-butyl ester (1.39 g, 7.23 mmol) was dissolved in a mixture oftrifluoroacetic acid (5 mL) and methylene chloride (10 mL) and stirredfor 45 min. The volatiles were removed in vacuo and the residue wasstirred with a mixture of ethyl acetate (100 mL) and water (100 mL).Sodium hydrogen carbonate (50 mL, saturated) was added and the phaseswere separated. The organic phase was dried (magnesium sulfate) and thesolvent removed in vacuo to afford 330 mg of(R)-N-methyl-2-methylamino-3-phenylpropionamide.

[0345]¹H-NMR (CDCl₃): d 2.1 (s(br), 3H); 2.32 (s, 3H); 2.77 (dd, 1H);2.81 (two s, 3H); 3.21 (dd, 1H); 3.32 (dd, 1H); 7.12 (s(br), 1H);7.20-7.34 (m, 5H).

[0346]N-Methyl-N{(1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl}carbamicAcid Tert-Butyl Ester:

[0347] Step G:

[0348] (R)-Tert-butoxycarbonyl-N-methylamino-3-(2-naphthyl)propionicacid (548 mg, 1.66 mmol) was dissolved in methylene chloride (5 mL);1-hydroxy-7-azabenzotriazole (227 mg, 1,66 mmol) was added along withN,N-dimethylformamide (2 mL).1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg,1.83 mmol) was added and the solution was stirred for 15 10 min.(R)-N-Methyl-2-methylamino-3-phenylpropionamide (320 mg, 1.66 mmol)dissolved in methylene chloride (4 mL) and diisopropylethylamine (0.28mL, 1.66 mmol) were added and the mixture was stirred overnight.Methylene chloride (50 mL) was added and the organic phase was washedwith water (100 mL), sodium hydrogensulfate (50 mL, 5%) and sodiumhydrogen carbonate (50 mL, saturated). The organic phase was dried(magnesium sulfate) and the solvent removed in vacuo. The residue waschromatographed (silica, 2×45 cm) using ethylacetate/methylene chloride(1:1) to afford 604 mg ofN-methyl-N-{(1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)-ethyl}carbamicacid tert-butyl ester.

[0349]¹H-NMR (CDCl₃): d 1.05, 1.31,1.56 (three s, 9H); 2.28-3.37(several m, 13H); 5.04, 5.17, 5.29, 5.48 (four dd, 2H); 7.05-7.79 (m,12H).

[0350](2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide:

[0351] Step H:

[0352]N-Methyl-N{(1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenyl-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (600 mg, 1.19 mmol) was stirred in trifluoroaceticacid/methylene chloride (1:1, 5 mL) for 10 min and the volatiles wereremoved in vacuo. The residue was stripped with diethylether (2×5 mL)and dissolved in methanol (2 mL) and mixed with sodium hydrogencarbonate (10 mL) and ethylacetate (15 mL). The organic phase wasseparated and dried (magnesium sulfate) to afford 420 mg of(2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide.

[0353]¹H-NMR (CDCl₃): (selected values) d 1.69 (s, 3H); 2.08 (d, 3H);2.54 (s, 3H); 2.76 (dd, 1H); 2.92 (dd, 1H), 3.12 (dd, 1H), 3.31 (dd,1H); 3.72 (dd, 1H), 4.95 (q (br), 1H); 5.50 (dd, 1H).

[0354]((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicAcid Tert-Butyl Ester:

[0355] Step I:

[0356] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (200mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (1 12 mg, 0.82 mmol) and1-ethyl-3-(3-s dimethylaminopropyl)-carbodiimide hydrochloride (173 mg,0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) andN,N-dimethylformamide (1 mL) and strirred for 15 min.N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide(332 mg, 0.82 mol) dissolved in methylene chloride (5 mL) anddiisopropylethylamine (0.14 mL) were added and the mixture was stirredovernight under nitrogen atmosphere. The mixture was diluted withmethylene chloride (50 mL), washed with water (50 mL), sodium hydrogencarbonate (30 mL, saturated), and sodium hydrogensulfate (30 mL, 5%).The phases were separated and the organic phase was dried with magnesiumsulfate and evaporated in vacuo. The residue was chromatographed(silica, 2×40 cm) to afford 450 mg of((3E)-1,1dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)-carbamicacid tert-butyl ester.

[0357]¹H-NMR (CDCl₃): (selected values) d 1.20, 1.22, 1.24, 1.30, 1.41,1.55 (six s, 15H), 4.30, 4.40 (two s (br), 1H); 5.08, 5.18, 5.32, 5.60,5.87 (five dd, 2H); 6.05 (dd, 1H); 6.75 (m, 1H).

[0358] Step J:

[0359]((3E)-1,1-Dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester (403 mg, 0.63 mmol) was stirred in a mixture oftrifluroacetic acdi (4 mL) and methylene chloride (4 mL) for 10 min. Thevolatiles were removed in vacuo and the crude product waschromatographed on silica (400 g) using a mixture of methylene chloride,ethanol and ammonia (25% in water) (80/18/2) as eluent. The isolatedproduct was dissolved in 3M hydrochloric acid in ethyl acetate andevaporated, then redissolved in methylene chloride and evaporated twiceto afford 140 mg of the title compound.

[0360]¹H-NMR (CDCl₃): d 1.05, 1.10, 1.15, 1.16 (fours, 6H); 2.07 (s(br); 3H); 5.12, 5.32, 5.40, 5.60, 5.91 (five dd, 2H); 6.05, 6.14 (twod, 1H); 6.80 (m, 1H)

[0361] HPLC: R_(t)=29.02 min (Method A1)

[0362] ESMS: m/z=529 (100%)(M+H)⁺

Example 2

[0363] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(((1R)-1-((2-methoxyethyl)-carbamoyl)-2-phenylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0364] This compound was prepared analogously to example 1.2-methoxyethylamine was substituted for methylamine in step E.

[0365]¹H-NMR (CDCl₃) (selected peaks, mixture of rotamers) d 1.05; 1.10(two d, 6H), 3.34 (s, 3H), 6.02 (d, 1H)

[0366] HPLC: R_(t)=30.47 min (Method A1)

[0367] PDMS: m/z=573.3 (100%) (M+H)⁺

Example 3

[0368] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(((1R)-1-((2S)-2-hydroxy-propylcarbamoyl)-2-phenylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0369] This compound was prepared analogously to example 1.(S)-2-hydroxypropylamine was substituted for methylamine in step E.

[0370]¹H-NMR (CDCl₃) (selected peaks, mixture of rotamers) d 3.90 (m,1H); 5.55 (dd, 1H); 5.58 (d, 1H)

[0371] HPLC: F =29.03 min (Method A1)

[0372] PDMS: m/z =573.5 (100%)(M+H)⁺

Example 4

[0373] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)amide:

[0374] This compound was prepared analogously to example 1.2-(methyl-amino)tetrahydrofuran was substituted for methylamine in stepE.

[0375]¹H-NMR (CDCl₃) (selected peaks, mixture of rotamers) d 1 .06, 1.09(two d, 6H); 2.78 (d, 2H); 5.25-5.62 (m, 2H); 6.05 (m, 1H)

[0376] HPLC: R_(t)=33.65 min (method A1)

Example 5

[0377] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(((1R)-1-((cyclopropylmethyl)-carbamoyl)-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0378] This compound was prepared analogously to example 1.Cyclopropylmethylamine was substituted for methylamine in step E.

[0379]¹H-NMR (CDCl₃) (selected peaks, mixture of rotamers) d 0.08-0.20(m, 2H); 1.05; 1.15 (twos, 6H); 6.02,6.05 (two d, 1H)

[0380] HPLC: R_(t)=35.7 m, (Method A1)

Example 6

[0381](2E)-3-(Azetidin-3-yl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)acrylamide:

[0382] 3-Carboxyazetidine-1-carboxylic Acid Tert-Butyl Ester.

[0383] Azetidine-3-carboxylic acid (1 0.0 g; 98.9 mmol) was dissolved intetrahydrofuran (1 20 mL) and water (20 mL). An aqueous solution ofsodium hydroxide (10 mL; 1 N) was added. Ditert butyl dicarbonate (25.9g; 118.7 mmol) was dissolved in tetrahydrofuran (80 mL) and addeddropwise to the reaction mixture. The reaction mixture was stirred for12 hours at room temperature and evaporated in vacuo. To the residue wasadded water (100 mL) and an aqueous solution of sodium hydroxide (100mL; 1N) and the aqueous phase was extracted with diethyl ether (2×100mL). The aqueous phase was acidified with an aqueous solution of sodiumis hydrogensulfate (1 M) until pH 2. Diethyl ether (200 mL) was addedand the organic phase was dried (magnesium sulfate) and evaporated invacuo to afford 20 g of 3-carboxyazetidine-1-carboxylic acid tert-butylester.

[0384]¹H-NMR (CDCl₃) d 1.43 (s, 9H); 3.37 (p, 1H); 4.14 (d, 4H); 10.05(s, 1H).

[0385] 3-Hydroxymethylazetidine-1-carboxylic Acid Tert-Butyl Ester.

[0386] 1-Carboxyazetidine-1-carboxylic acid tert-butyl ester (5.0 g;24.8 mmol) was dissolved in dry tetrahydrofuran. Triethylamine (4.1 mL;29.8 mmol) was added and the reaction mixture was cooled to 0° C. Ethylchloroformate (2.4 mL; 24.8 mmol) was added and the reaction mixture wasstirred for 40 min at 0° C. The reaction mixture was filtered and thefilter cake was washed with dry tetrahydrofuran (30 mL). The combinedfiltrates were cooled to 0° C. and lithium borohydride (2.0 M intetrahydrofuran; 31 mL; 62.1 mmol) was added dropwise to the reactionmixture and it was then heated to room temperature and stirred for 12hours. The reaction mixture was cooled to 0° C. and methanol (10 mL) wasadded dropwise. An aqueous solution of sodium hydrogen carbonate (100mL; 10%) was added and the reaction mixture was extracted with ethylacetate (4×100 mL). The combined organic phases were washed with asaturated solution of sodium hydrogen carbonate (100 mL), dried(magnesium sulfate) and evaporated in vacuo to afford 3.43 g of3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester.

[0387]¹H-NMR (CDCl₃) d: 1.43 (s, 9H); 2.7 (p, 1H); 3.63-3.70 (m, 2H),3.74 (d, 1H); 3.88 (d, 1H); 3.94.0 (m, 2H).

[0388] 3-Formylazetidine-1-carboxylic Acid Tert-Butyl Ester.

[0389] Oxalyl chloride (2.1 mL; 24.0 mmol) was dissolved in methylenechloride (30 mL) and cooled to −78° C. Dimethyl sulfoxide (2.3 mL; 32.0mmol) was added. A solution of 3-hydroxymethylazetidine-1-carboxylicacid tert-butyl ester (3.0 g; 16.0 mmol) in methylene chloride (20 mL)was added dropwise to the reaction mixture. Triethyl amine (11.1 mL;80.1 mmol) was added and the reaction mixture was heated to roomtemperature. Methylene chloride (200 mL) and hydrochloric acid (200 mL;1 N) was added. The aqueous phase was extracted with methylene chloride(100 mL). The combined organic phases were washed with saturated sodiumhydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated invacuo. The residue was chromatographed on silica (3×30 cm) using ethylacetatelheptane (4:1) as eluent to afford 1.11 g of3-formylazetidine-1-carboxylic acid tert-butylester.

[0390]¹H-NMR (CDCl₃) d: 1.43 (s, 9H); 3.37 (p, 1H); 4.054.15 (m,4H)>9.82 (s, 1H).

[0391] 3-((E)-2-Ethoxycarbonylvinyl)azetidine-1-carboxylic AcidTert-butylester:

[0392] Triethyl phosphonoacetate (1.9 mL; 9.72 mmol) was dissolved intetrahydrofuran (30 mL). Potassium tert-butoxide (1.1 g; 9.72 mmol) wasadded portionwise. 3-Formylazetidine-1-car-boxylic acid tert-butyl ester(1.0 g; 5.40 mmol) was dissolved in tetrahydrofuran (6 mL) and added tothe reaction mixture. The reaction mixture was stirred for 1 hour atroom temperature. Ethyl acetate (100 mL) and hydrochloric acid (100 mL;1 N) were added and the phases were separated. The aqueous phase wasextracted with ethyl acetate (2×50 mL) and the combined organic phaseswere washed with saturated sodium hydrogen carbonate (100 mL), dried(magnesium sulfate) and evaporated in vacuo. The residue waschromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) aseluent to afford 1.0 g of3-((E)-2-ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butylester.

[0393]¹H-NMR (CDCl₃) d: 1.24 (t, 3H); 1.48 (s, 9H); 3.22-3.32 (m, 1H);3.75 (dd, 2H); 4.08 (t, 2H); 4.15 (q, 2H); 5.8 (d, 1H); 7.02 (dd, 1H).

[0394] 3-((E)-2-Carboxyvinyl)azetidine-1-carboxylic Acid Tert-ButylEster:

[0395] 3-((E)-2-Ethoxycarbonylvinyl)azetidime-1-carboxylic acidtert-butyl ester (0.95 g; 3.72 mmol) was dissolved in 1,4dioxane (15mL). Lithium hydroxide (0.098 g; 4.1 mmol) and water (10 mL) were added.The reaction mixture was stirred for 12 hours at room temperature. Water(70 mL) was added and the reaction mixture was washed with tert-butylmethyl ether (70 mL) and the phases were separated. The aqueous phasewas adjusted to pH 2 with an aqueous solution of sodium hydrogensulfate(10%) and extracted with tert-butyl methylether (3×70 mL). The combinedorganic phases were dried (magnesium sulfate) and the solvent evaporatedin vacuo to afford 0.76 g of3-((E)-2-carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester.

[0396]¹H-NMR (CDCl₃) d :1.43 (s, 9H); 3.31-3.42 (m, 1H); 3.84 (dd, 2H);4.16 (t, 2H); 5.88 (d, 1H); 7.1 8(dd, 1H).

[0397]3-(2-(Methyl-((1R)-1-(methyl-((1R)-1-(methylcarbamoyl)-2phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylicAcid Tert-Butyl Ester:

[0398] 3-((E)-2-Carboxyvinyl)azetidine-1-carboxylic acid tert-butylester (0.28 g; 1.24 mmol) was dissolved in methylene chloride (3 mL).1-Hydroxy-7-azabenzotriazole (0.17 g; 1.24 mmol) andN-(3dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g;1.36 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.N-Methyl-2-methylamino-N-(1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide(0.50 g; 1.24 mmol) (prepared as in example 1) was dissolved inmethylene chloride (3 mL) and added to the reaction mixture.Ethyldiisopropylamine (0.21 mL; 1.24 mmol) was added and the reactionmixture was stirred for 12 hours at room temperature. Methylene chloride(20 mL) was added and the reaction mixture was washed with water (10mL), an aqueous solution of sodium hydrogen sulfate (10 mL; 10%), anaqueous solution of sodium hydrogen carbonate (10 mL; sat.) and water(10 mL). The organic phase was dried (magnesium sulfate) and evaporatedin vacuo. The residue was chromatographed on silica (2,5×20 cm) using2.5%(7% ammonia in ethanol) in methylene chloride as eluent to afford0.49 g of3-((E)-2-(methyl((1R)-1-(methyl((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylicacid tert-butyl ester.

[0399]¹H-NMR (CDCl₃) d 1.41, 1.45 (two s, 9H); 1.55, 1.58 (two s, 3H);2.21 (d, 1H); 2.54 (s, 1H); 2.72-2.81 (m, 3H); 2.83-2.96 (m, 1H); 3.0(d, 3H); 3.02-3.42 (m, 3H); 3.68-3.82 (m, 2H); 4.06 (q, 1H); 4.14 (q,1H); 5.11, 5.31 (two m, 1H); 5.58, 5.88 (two dd, 1H); 6.03 (d, 1H);6.88, 6.91 (two dd, 1H); 7.0-7.23 (m, 5H); 7.3-7.58 (m, 3H); 7.65-7.81(m, 3H).

[0400]3-((E)-2-(Methyl((1R)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylicacid tert-butyl ester (0.45 g; 0.73 mmol) was dissolved in methylenechloride (2 mL). Trifluoroacetic acid (2 mL) was added and the reactionmixture was stirred for 7 min. Methylene chloride (50 mL), an aqueoussolution of sodium hydrogen carbonate/sodium carbonate (50 mL; pH 9) andsodium carbonate were added to the reaction mixture until pH 8. Theorganic phase was dried (magnesium sulfate) and evaporated in vacuo toafford 0.29 g of the title compound.

[0401]¹H-NMR (CDCl₃) d (selected peaks): 2.25, 2.26, 2.28 (three s, 3H);5.12, 5.31, 5.59, 5.88 (four dd, 2H); 6.00 (dd, 1H; J₁=15 Hz; J₂=2.5Hz); 6.91 (m, 1H).

[0402] ESMS: m/z 513.2 (M+H)⁺

[0403] HPLC: r_(t)=29.40 min (A1)

Example 7

[0404](2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(methyl((piperidin-4-ylidene)acetyl)amino)-3-(2-naphthyl)propionamide:

[0405] 4-Oxopiperidine-1-carboxylic Acid Tert-Butyl Ester:

[0406] Piperidin-4-one hydrochloride (10.0 g; 74.3 mmol) was dissolvedin tetrahydrofuran (100 mL) and an aqueous solution of sodium hydroxide(74 mL; 74.3 mmol; 1 N) was added. Di-tert-butyl dicarbonate (19.5 g;89.2 mmol) was dissolved in tetrahydrofuran (50 mL) and added dropwise.The reaction mixture was stirred for 12 hours at room temperature andevaporated in vacuo. The residue was extracted with ethyl acetate (3×100mL). The combined organic phases were washed with an aqueous solution ofsodium hydrogen sulfate (100 mL; 10%), dried (magnesium sulfate) andevaporated. The residue was crystallised from heptane and dried in vacuoto afford 10.9 g of 4-oxopiperidine-1-carboxylic acid tert-butyl ester.

[0407]¹H-NMR (CDCl₃) d: 1.50 (s, 9H); 2.44 (t, 4H); 3.71 (t, 4H).

[0408] 4-Carboxymethylenepiperidine-1-carboxylic Acid Tert-Butyl Ester:

[0409] 4-Oxopiperidine-1-carboxylic acid tert-butyl ester (8.0 g; 40.2mmol) was dissolved in toluene (80 mL). Carboethoxymethylenetriphenylphosphorane (17.5 g; 50.2 mmol) was added and the reactionmixture was heated 12 hours at reflux. The reaction mixture wasevaporated in vacuo and the residue was chromatographed on silica(4.5×30 cm) using diethyl ether/heptane (1:1) as eluent to afford 9.5 g(35.7 mmol) of 4-Ethoxycarbonylmethylenepiperidine-1-carboxylic acidtert-butyl ester, which was dissolved in 1,4-dioxane and cooled to 0° C.Lithium hydroxide (2.73 g; 114 mmol) was dissolved in water (20 mL) andadded. The reaction mixture was stirred for 12 hours at roomtemperature. Ethyl acetate (200 mL) and water (100 mL) was added. Sodiumhydrogen sulfate (10%; aqueous solution) was added to pH 2. The organicphase was washed with water (100 mL), dried (magnesium sulfate) andevaporated in vacuo to afford 5.49 g of4-carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester.

[0410]¹H-NMR (CDCl₃) d: 1.47 (s, 9H); 2.31 (t, 2H), 2.94 (t, 2H); 3.50(dt, 4H); 5.75 (s, 1H); 10.75 (s, 1H).

[0411]4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylicAcid Tert-Butyl Ester:

[0412] 4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester(0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g;1.36 mmol) was added. The reaction mixture was stirred for 15 min atroom temperature.(2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide(0.5 g; 1.24 mmol, prepared as in example 1) was added and the reactionmixture was stirred for 12 hours at room temperature. The reactionmixture was washed with water (50 mL), an aqueous solution of sodiumhydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogencarbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated invacuo. The residue was chromatographed on silica (2×20 cm) using ethylacetate as eluent to afford 0.270 g of4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylicacid tert-butyl ester.

[0413]¹H-NMR (CDCl₃) d: 1.42 (s, 3H); 1.45 (s, 3H); 1.52, 1.55 (two s,9H); 2.05-2.18 (m, 1H); 2.34-2.42 (m, 2H); 2.71-2.80 (m, 3H); 2.80-2.89(m, 1H); 2.90-3.01 (m, 3H); 3.02-3.36 (m, 3H); 5.16, 5.36 (two m, 1H);5.57, 5.90 (two t, 1H); 6.90-7.25 (m, 6H); 7.28-7.53 (m, 3H); 7.61-7.82(m, 3H).

[0414]4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylicacid tert-butyl ester (0.27 g; 0.43 mmol) was dissolved in methylenechloride (8 mL) and trifluoroacetic acid (8 mL) was added. The reactionmixture was stirred for 10 min. Methylene chloride (30 mL) and anaqueous solution of sodium hydrogen carbonate (10 mL; satturated) wereadded. Solid sodium hydrogen carbonate was added to pH 8. The organicphase was dried (magnesium sulfate) and evaporated in vacuo to afford0.17 g of the title compound.

[0415]¹H-NMR (CDCl₃) d (rotamers, selected peaks): 5.18; 5.38; 5.58;5.90 (four dd, 2H); 5.49, 5.52 (two s, 1H)

[0416] ESMS: m/z 527.4 (M+H)⁺

[0417] HPLC: r_(t)=28.62 min (Method A1)

Example 8

[0418](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide:

[0419]Methyl-((1R)-2-phenyl-1-((tetrahydrofuran-2-yl)methyl)-carbamoyl)ethyl)carbamicAcid Tert-Butyl Ester:

[0420] (2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropionic acid(5.0 g; 17.9 mmol) was dissolved in methylene chloride (50 mL).1-Hydroxybenzotriazole (2.42 g; 17.9 mmol) andN-(3dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.58 g;18.8 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature. ((Tetrahydrofuran-2-yl)methyl)amine (1.72 g; 17.1mmol) and diisopropyl-ethylamine (3.2 mL; 18.8 mmol) were added and thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (200 mL) was added and the reaction mixture was washed withwater (100 mL), an aqueous solution of sodium hydrogen sulfate (10%, 100mL), an aqueous solution of sodium hydrogen carbonate (saturated, 100mL), water (100 mL) and dried (magnesium -sulfate). The solvent wasremoved in vacuo and the residue was chromatographed on silica (3×40 cm)using ethyl acetate/heptane (2:1) as eluent to afford 5.62 g ofmethyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamicacid tert-butyl ester.

[0421]¹H-NMR (CDCl₃) d: 1.28; 1.38 (two s, 9H); 1.40-1.57 (m, 1H);1.76-2.01 (m, 3H); 2.70-2.80 (m, 3H); 2.86-2.96 (m, 1H); 3.15-3.61 (m,3H); 3.67-3.75 (m, 1H); 3.76-3.85 (m, 1H); 3.86-3.99 (m, 1H); 4.72; 4.92(two m, 1H); 6.26; 6.4 (two m, 1H); 7.14-7.29 (m, 5H). ;(2R)-2-Methylamino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide:

[0422]Methyl-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)carbamicacid tert-butyl ester (5.5 g; 15.2 mmol) was dissolved in methylenechloride (20 mL) and trifluoroacetic acid (20 mL) was added. Thereaction mixture was stirred for 1 hour at room temperature. Methylenechloride (100 mL) and an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9, 50 mL) were added and solid sodiumhydrogen carbonate was added until pH 8. The aquous phase was extractedwith methylene chloride (100 mL) and the combined organic phases weredried (magnesium sulfate). The solvent was removed in vacuo to afford3.62 g of(2R)-2-Methyl-amino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide.

[0423]¹H-NMR (CDCl₃) d: 1.46-1.57 (m, 1H); 1.62 (s, 1);1.82-2.01 (m,3H); 2.29 (d, 3H); 2.65-2.74 (m, 1H); 3.16-3.27 (m, 3H); 3.49-3.58 (m,1H); 3.7-3.78 (m, 1H); 3.8-3.88 (m, 1H); 3.9-3.98 (m, 1H); 7.19-7.34 (m,5H); 7.43 (s, 1H).

[0424]Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)-carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicAcid Tert-Butyl Ester:

[0425] (2R)-2-(tert-Butoxycarbonylmethylamino)-3-(2-naphthyl)propionicacid (4.14 g; 12.58 mmol) was dissolved in methylene chloride (40 mL).1-Hydroxy-7-azabenzotriazole (1.71 g; 12.6 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.52 g;13.2 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-2-Methylamino-3-phenyl-N-((2-tetrahydrofuranyl)methyl)propionamide(3.0 g; 11.4 mmol) and diisopropylethylamine (2.15 mL; 12.6 mmol) wereadded. The reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (200 mL) was added. The reaction mixturewas washed with water (200 mL), an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9, 100 mL), an aqueous solution of sodiumhydrogen sulfate (10%, 100 mL), water (100 mL) and dried (magnesiumsulfate). The solvent was removed in vacuo and the residue waschromatographed on silica (4×40 cm) using ethyl acetate/heptane (1:1) aseluent to afford 4.27 g ofmethyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydro-furan-2-yl)methyl)-carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester.

[0426]¹H-NMR (CDCl₃) d: 1.01 (s, 2H); 1.24 and 1.27 (two s, 9H);1.54-1.64 (m, 1H); 1.65-1.99 (m, 2H); 2.24 (t, 2H); 2.7-2.8 (m, 1H);2.82; 2.88 (two d, 3H); 2.95 (s, 3H); 3.00-3.44 (m, 2H); 2.45-2.98 (m,3H); 4.96-5.10 (m, 1H); 5.30-5.45 (m, 1H); 5.95; 6.17 (two m, 1H);7.02-7.10 (m, 1H); 7.11-7.23 (m, 4H); 7.34-7.47 (m, 3H); 7.65 (s, 1H);7.68-7.8 (m, 4H).

[0427](2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide:

[0428]Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)-carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester. (4.2 g; 7.32 mmol) was dissolved in methylenechloride (20 mL) and trifluoroacetic acid (20 mL) was added. Thereaction mixture was stirred for 15 min at room temperature. Methylenechloride (100 mL), an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9, 100 mL) and solid sodium hydrogencarbonate were added to the reaction mixture until pH 8. The organicphase was dried (magnesium sulfate) and evaporated in vacuo to afford3.5 g of(2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide.

[0429](1,1-Dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)-ethyl)carbamoyl)methoxy)ethyl)carbamicacid tert-butyl ester:

[0430] (2-tert Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.5 g;2.06 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.2 g; 1.51 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.30 g;1.58 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.(2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide(0.65 g; 1.37 mmol) and diisopropylethylamine (0.26 mL; 1.51 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (100 mL) was added. The reaction mixturewas washed with an aqueous solution of sodium hydrogen sulfate (10%; 50mL), an aqueous solution of sodium hydrogen carbonate (sat; 50 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was filtered through silica to afford 0.76 g of(1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamicacid tert-butyl ester.

[0431]¹H-NMR (CDCl₃) d: 0.89-0.95 (m, 3H); 1.1; 1.15 (two s, 3H); 1.41;1.43 (two s, 9H); 1.68-2.0 (m, 4H); 2.22 (s, 1H); 2.26 (s, 1H); 2.82;2.86 (two d, 3H); 2.88-2.97 (m, 2H); 2.99 (d, 3H); 3.06-3.36 (m, 3H);3.45-3.95 (m, 5H); 5.05; 5.16 (two m, 1H); 5.33 (s, 1H); 5.37-5.5 (m,1H); 5.81; 5.91 (two q, 1H); 6.89-7.1 (m, 2H); 7.13-7.24 (m, 4H);7.34-7.47 (m, 3H); 7.63 (s, 1H); 7.69-7.79 (m, 3H).

[0432] (11-Dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamicacid tert-butyl ester (0.76 g; 1.08 mmol) was dissolved in methylenechloride (5 mL) and trifluoroacetic acid (5 mL) was added. The reactionmixture was stirred for 10 min at room temperature. Methylene chloride(50 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 50 mL) and solid sodium hydrogen carbonate was added tothe reaction mixture until pH 8. The aqueous phase was extracted withmethylene chloride (2×50 mL) and the combined organic layers were dried(magnesium sulfate) and evaporated in vacuo to afford 0.6 g of the titlecompound.

[0433]¹H-NMR (CDCl₃) d (rotamers; selected peaks): 1.00; 1.02; 1.03;1.09 (four s; 6H); 5.07; 5.15; 5.78; 5.97 (four dd, 1H); 5.42 (m; 1H).

[0434] ESMS: m/z 602.9 (M+H)⁺

[0435] HPLC: R_(t)=33.30 (Method A1)

Example 9

[0436] (2E)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((2-tetra-hydrofuranyl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0437] (1, 1-Dimethyl-3-oxobutyl)carbamic Acid Tert-Butylester:

[0438] Diacetonamine hydrogen oxalate (30.0 g; 146 mmol) was suspendedin tetrahydrofuran (400 mL). An aqueous solution of sodium hydroxide (1N; 146 mL) was added. Di-tert-Butyl dicarbonate (38.3 g; 175 mmol) wasdissolved in tetrahydrofuran (100 mL) and added dropwise to the reactionmixture. The reaction mixture was stirred for 2 hours at roomtemperature. Sodium hydroxide (1 N; 146 mL) was added and the reactionmixture was stirred for 12 hours at room temperature. Water (200 mL) andethyl acetate (200 mL) were added. The aqueous phase was extracted withethyl acetate (4×200 mL). The combined organic phases were dried(magnesium sulfate) and the solvent was removed in vacuo. The residuewas chromatographed on silica (6×40 cm) using ethyl acetate/heptane(1:3) as eluent to afford 28.4 g of (1,1-dimethyl-3-oxobutyl)carbamicacid tert-butyl ester.

[0439]¹H-NMR (CDCl₃) d 1.34 (s, 6H); 1.42 (s, 9H); 2.14 (s, 3H); 2.86(s, 2H); 4.85 (s, 1H).

[0440] (E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic AcidEthylester:

[0441] Triethyl phosphono acetate (4.7 g; 20.9 mmol) was dissolved intetrahydrofuran (36 mL). Potassium tert-butoxide (2.3 g; 20.9 mmol) wasadded and the reaction mixture was stirred for 40 min at roomtemperature.

[0442] (1,1-dimethyl-3-oxobutyl)carbamic acid tert-butylester (2.5 g;11.6 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwiseto the reaction mixture which was heated to reflux for 12 h. Ethylacetate (100 mL) and hydrochloric acid (1 N; 100 mL) were added and thephases were separated. The aqueous phase was extracted with ethylacetate (3×50 mL). The combined organic phases were washed with anaqueous solution of sodium hydrogen carbonate (saturated; 100 mL), dried(magnesium sulfate) and evaporated in vacuo. The residue waschromatographed on silica (3×40 cm) using ethyl acetate/heptane (1:2) aseluent to afford 2.0 g of(E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethylester.

[0443]¹H-NMR (CDCl₃) d 1.25 (t, 3H); 1.30 (s, 6H); 1.44 (s, 9H); 2.21(s, 3H); 2.58 (s, 2H); 4.14 (q, 2H); 4.48 (s, 1H); 5.65 (s, 1H).

[0444] (2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2enoic Acid:

[0445] (E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acidethylester (1.95 g; 6.83 mmol) was dissolved in 1,4-dioxane (25 mL) andwater (15 mL). Lithium hydroxide (0.18 g; 7.52 mmol) was added and thereaction mixture was stirred for 12 hours at room temperature. Water(150 mL) and tert-butyl methyl ether (150 mL) was added. The aqueousphase was diluted with an aqueous solution of sodium hydrogensulfate(10%) until pH 2,5 and extracted with tert-butyl methylether (3×100 mL).The combined organic phases were dried (magnesium sulfate) andevaporated in vacuo. The residue was recrystallized from heptane (20 mL)to afford 0.6 g of(2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid.

[0446]¹H-NMR (CDCl₃) d 1.29 (s, 6H); 1.44 (s, 9H); 2.23 (s, 3H); 2.62(s, 2H); 4.45 (s, 1H); 5.66 (s, 1H).

[0447] ((3E)-1, 1,3-Trimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)-ethyl)carbamoyl)but-3-enyl)carbamicAcid Tert-Butyl Ester:

[0448] (2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid (0.3g; 1.17 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.12 g; 0.85 mmol) andN-(3dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g;0.89 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0449](2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide(0.37 g; 0.78 mmol) and diisopropylethylamine (0.15 mL; 0.85 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (50 mL) was added and the reactionmixture was washed with water (50 mL), an aqueous solution of sodiumhydrogen carbonate (saturated; 30 mL), an aqueous solution of sodiumhydrogen sulfate (10%; 30 mL), water (30 mL), and dried (magnesiumsulfate). The solvent was removed in vacuo and the residue waschromatographed on silica (2.5×30 cm) using ethyl acetate/heptane (2:1)as eluent to afford 0.21 g of((3E)-1,1,3-trimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butylester.

[0450]¹H-NMR (CDCl₃)(rotamers; selected peaks) d: 1.15; 1.21; (two s;6H); 1.30; 1.41 (two s; 9H).

[0451]((3E)-1,1,3-Trimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)-carbamoyl)but-3-enyl)carbamicacid tert-butylester (0.20 g; 0.28 mmol) was dissolved in methylenechloride (3 mL). Trifluoroacetic acid (3 mL) was added and the reactionmixture was stirred for 6 min at room temperature. Methylene chloride(50 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 50 mL) and solid sodium hydrogen carbonate were addedto the reaction mixture to pH 8. The organic phase was dried (magnesiumsulfate) and evaporated in is vacuo to afford 0.155 g of the titlecompound.

[0452]¹H-NMR (CDCl₃)(rotamers; selected peaks) d: 1.36; 1.41 (two s;6H); 4.38; 5.12; 5.31; 6.25 (four m; 2H).

[0453] ESMS: m/z : 613.7 (M+H)⁺

[0454] HPLC: R_(t)=34.47 (Method A1)

Example 10

[0455] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide:

[0456] (2R)-3-Benzyloxy-2-(tert-butoxyarbonylmethylamino)propionic Acid:

[0457] (2R)-3-Benzyloxy-2-tert-butoxycarbonylaminopropionic acid (7.0 g;23.7 mmol) was dissolved in dry tetrahydrofuran and iodomethane (11.9mL; 189 mmol) was added. The reaction mixture was cooled to OIC andsodium hydride (60% in mineral oil) (2.73 g; 71 mmol) was added. Thereaction mixture was left 3 days without stirring at 0° C. Citric acid(5%) was added until pH 2.5. Tetrahydrofuran was removed in vacuo andthe residue was extracted with methylene chloride (3×100 mL). Theorganic phase was dried (magnesium sulfate) and evaporated in vacuo. Theresidue was dissolved in diethyl ether (20 mL) and dicyclohexylamine (10mL) and is heptane (100 mL) were added. The reaction mixture was left 3days without stirring at 0° C. The reaction mixture was filtered toafford 5.78 g of(2R)-3-benzyloxy-2-(tert-butoxycarbonylmethylamino)propionic acid.

[0458]¹H-NMR (CDCl₃) d 1.40; 1.42 (two s, 9H); 2.91; 2.97 'two s, 3H);3.90, 3.91 (two s, 2H); 4.55 (two d, 2H); 3.83; 4.90 (two t; 1H);7.25-7.38 (arom. 5H).

[0459]N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)N-methylcarbamicAcid Tert-Butyl Ester:

[0460] (2R)-3-Benzyloxy-2-(tert-butoxycarbonylmethylamino)propionic acid(0.39 g; 1.25 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.16 g; 1.14 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.23 g;1.20 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0461] N-methyl-2-methylamino-3-phenyl-propionamide (0.2 g; 1.04 mmol,prepared as in example 1) and diisopropylethylamine (0.2 mL; 1.14 mmol)were added and the is reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (30 mL) was added. The reaction mixturewas washed with water (50 mL), an aqueous solution of sodium hydrogencarbonate (saturated, 30 mL), an aqueous solution of sodium hydrogensulfate (10%, 30 mL) and water (30 mL) and dried (magnesium sulfate).The solvent was removed in vacuo and the residue was chromatographed onsilica (2.5×30 cm) using ethyl acetate/heptane (2:1) as eluent to afford0.241 g ofN-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

[0462]¹H-NMR (CDCl₃) (selected peaks) d 1.42; 1.45 (two s; 9H); 2.71;2.78 (two d, 3H); 2.84; 2.92 (twos; 3H); 4.11; 4.30 (two d; 1H); 4.43;4.57 (two t; 1H)

[0463](2R)-3-Benzyloxy-N-methyl-2-(methylamino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide:

[0464]N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)N-methylcarbamicacid tert-butyl ester (0.23 g; 0.476 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (3 mL) was added. The reactionmixture was stirred for 10 min at room temperature. Methylene chloride(50 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9) and sodium hydrogen carbonate (solid) were added to thereaction mixture until pH 9. The organic phase was dried (magnesiumsulfate) and evaporated in vacuo to afford 0.182 g of(2R)-3-Benzyloxy-N-methyl-2-(methylamino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide.

[0465]¹H-NMR (CDCl₃) (selected data for major rotamer) d 2.18 (d, 3H);2.92-2.95 (d and s, 6H); 3.31-3.45 (m, 4H); 3.65 (t, 1H); 4.45 (d, 1H);4.48 (d, 1H); 4.65 (dd; 1H).

[0466]((3E)-4-(N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicAcid Tert-Butyl Ester:

[0467] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(0.12 g; 0.49 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.07 g; 0.49 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.1 g;0.51 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-3-Benzyloxy-N-methyl-2-(methyl-amino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide(0.17 g; 0.44 mmol) and diisopropylethylamine (0.084 mL; 0.49 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. The reaction mixture was extracted with an aqueous solutionof sodium hydrogen carbonate (saturated; 30 mL) and an aqueous solutionof sodium hydrogen sulfate (10%; 30 mL) and dried (magnesium sulfate).The solvent was removed in vacuo and the residue was chromatographed onsilica (2.5×30 cm) using methylene chloride/ethyl acetate (1:1) aseluent to afford 0.275 g of((3E)-4-(N-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.

[0468]¹H-NMR (CDCl₃) (selected data for major rotamer) d 1.25 (s, 3H);1.27 (s, 3H); 1.41 (s, 9H); 2.05 (s, 3H); 2.78 (d, 3H); 3.07 (s, 3H);4.32 (d, 1H); 4.41 (d, 1H); 5.05 (dd, 1H); 5.51 (dd, 1H); 6.30 (d; J=17Hz; 1H); 6.79 (m, 1H).

[0469]((3E)-4-(N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (0.275 g; 0.452 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (3 mL) was added and thereaction mixture was stirred for 7 min at room temperature. Methylenechloride (30 mL), an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate(solid) were added to the reaction mixture until pH 8. The organic phasewas dried (magnesium sulfate) and evaporated in vacuo to afford 0.13 gof the title compound.

[0470]¹H-NMR (CDCl₃) (selected data for major rotamer) d 1.27 (s, 3H);1.28 (s; 3H); 2.84 (d, 3H); 2.95 (s, 3H); 3.08 (s, 3H); 4.32 (d; 1H);4.40 (d, 1H); 5.12 (dd, 1H); 6.34 (d, J=18 Hz, 1H).

[0471] ESMS: m/z 509.7 (M+H)⁺

[0472] HPLC: R_(t)=23.45 min (Method A1)

Example 11

[0473](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-((1R)-1-((cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)-propionamide:

[0474](2-((N-((1R)-1-(N-((1R)-1-(Cyclopropylmethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamicAcid Tert-Butylester:

[0475] (2-tert-Butoxycarbonylamino-2-methylpropoxy) acetic acid (0.36 g;1.49 mmol) was dissolved in methylene chloride (5 mL).1-Hydroxy-7-azabenzotriazole (0.2 g; 1.49 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.3 g;1.56 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0476](2R)-N-((1R)-1-((Cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(0.60 g; 1.35 mmol) and diisopropylethylamine (0.26 mL; 1.49 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (30 mL) was added. The reaction mixturewas washed with an aqueous solution of sodium hydrogen carbonate(saturated; 30 mL) and an aqueous solution of sodium hydrogen sulfate(10%; 30 mL) and dried (magnesium sulfate). The solvent was removed invacuo and the residue was chromatographed on silica (3.5×40 cm) usingethyl acetate/heptane (1:1) as eluent to afford 0.64 g of(2-((N-((1R)-1-(N-((1R)-1-((cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamicacid tert-butyl ester.

[0477]¹H-NMR (CDCl₃) (rotamers, selected peaks) d : -0.11 (m 1H); 0.19(m, 1H); 0.45 (m, 1H); 0.95; 1.17; 1.25; 1.27; 1.40; 1.43; 1.58 (sevens, 15H); 2.29; 2.81; 2.91; 3.03 (four s, 6H).

[0478](2-((N-((1R)-1-(N-((1R)-1-((Cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)methoxy)-1,1-di-methylethyl)carbamicacid tert-butylester (0.64 g; 0.951 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (3 mL) was added. The reactionmixture was stirred for 5 min. Methylene chloride (25 mL), an aqueoussolution of sodium hydrogen carbonate/sodium carbonate (pH 9; 25 mL) andsodium hydrogen carbonate (solid) were added to the reaction mixture topH 8. The organic phase was dried (magnesium sulfate) and evaporated invacuo to afford 0.48 g of the title compound.

[0479]¹H-NMR (CDCl₃) (rotamers, selected peaks) d: 0.55; 0.57; 0.80;0.82 (four s, 6H); 2.09; 2.62; 2.75; 2.84 (four s; 6H); 3.68; 3.82 (twod, 2H together with a singlet at

[0480]3.69); 4.92; 5.22; 5.30; 5.38; 5.65 (five dd, 3H);

[0481] ESMS: m/z 572.0 (M+H)⁺

[0482] HPLC: R_(t)=35.52 min (Method A1)

Example 12

[0483](2R)-2-(((2-Amino-2-methylpropoxy)acetyl)methylamino)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide:

[0484](2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-fluorophenyl)propionicAcid:

[0485] (The N-methylation in this and other examples in this inventionmay be performed as in Can. J. Chem. 1977, 55, 906).

[0486] (2R)-2-tert-Butoxycarbonylamino-3-(2-fluorophenyl)propionic acid(5.0 g; 17.5 mmol) was dissolved in dry tetrahydrofuran. Iodomethane(7.2 mL; 1 15 mmol) was added and the reaction mixture was cooled to 0°C. Sodium hydride (60% susp. in oil; 1.41 g; 42.0 mmol) was added andthe reaction mixture was stirred for 12 hours is at room temperature.Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise.The ethyl acetate was removed in vacuo and the residue was diluted withether (30 mL) and water (100 mL). The organic phase was extracted withan aqueous solution of sodium hydrogen carbonate (aqueous; 50 mL). Tothe combined aqueous layers was added citric acid (5%) until pH 3 andethyl acetate (3×50mL) was added and the phases were separated. Thecombined organic layers were washed with water (2×50 mL), an aqueoussolution of sodium thiosulfate (5%; 2×50 mL) and water (50 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas dissolved in diethyl ether (10 mL). Dicyclohexylamine (9.0 mL) wasadded. The reaction mixture was filtered to afford 5.57 g of(2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-2-fluorophenyl)propionicacid as a dicyclohexylammonium salt.

[0487]¹H-NMR (CDCl₃) d 1.27; 1.35 (two s, 9H); 2.21; 2.25 (two s, 3H);3.03 (m, 2H); 4.26; 4.37 (two dd, 1H); 6.9-7.3 (arom 4H).

[0488]N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamicAcid Tert-Butylester:

[0489](2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-fluorophenyl)propionicacid as a dicyclohexylammonium salt (5.57 9; 18.73 mmol) was dissolvedin methylene chloride (30 mL) and washed with an aqueous solution ofsodium hydrogen sulfate (10%; 30 mL). The organic phase was dried(magnesium sulfate) and filtered. 1-Hydroxybenzotriazole hydrate (2.53g; 18.73 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (3.75 g; 19.6 mmol) were added to the filtrate and themixture was stirred for 15 min at room temperature. Methylamine (40% inmethanol; 0.53 g; 17.0 mmol) and diisopropylethylamine (3.2 mL; 18.7mmol) were added and the reaction mixture was stirred for 12 hours atroom temperature. The reaction mixture was washed with an aqueoussolution of sodium hydrogen carbonate (50 mL) and an aqueous solution ofsodium hydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). Thesolvent was removed in vacuo and the residue was chromatographed onsilica (3.5×40 cm) using ethyl acetate/heptane (2:1) as eluent to afford2.4 g ofN-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

[0490]¹H-NMR (CDCl₃) d: 1.25; 1.35; 1.38 (three s, 9H); 2.74 (s, 3H);2.75 (d, 3H); 2.80-3.55 (m, 2H); 4.35; 4.82; 5.00; 5.12 (four dd;6.9-7.3 (arom, 4H).

[0491] (2R)-3-(2-Fluorophenyl)-N-methyl-2-(methylamino)-propionamide:

[0492]N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamicacid tert-butylester (2.4 g; 7.73 mmol) was dissolved in methylenechloride. Trifluoroacetic acid (1 0 mL) was added and the reactionmixture was stirred for 30 min at room temperature. Methylene chloride(30 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 8. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 1.1 g of(2R)-3-(2-fluorophenyl)-N-methyl-2-(methylamino)-propionamide.

[0493] H-NMR (CDCl₃) d 2.31 (s, 3H); 2.80 (d, 3H); 2.86 (dd, 1H); 3.17(dd, 1H); 3.28 (dd, 1H); 7.0-7.30 (arom. 4H).

[0494]N-((1R)-1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)-ethyl)-N-methylcarbamicacid tert-butyl ester.

[0495] Tert-Butoxycarbonylaminoacetic acid (0.18 g; 2.39 mmol) wasdissolved in methylene chloride (20 mL). 1-Hydroxybenzotriazole (0.32 g;2.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.55 g; 2.87 mmol) were added and the reaction mixturewas stirred for 15 min at room temperature.(2R)-3-(2-Fluorophenyl)-N-methyl-2-(methylamino)propionamide (1.0 g;4.78 mmol) and diisopropylethylamine (0.9 mL; 5.26 mmol) was added andthe reaction mixture was stirred for 12 hours at room temperature. Amixture of 2-(tert-butoxycarbonylmethylamino)-3-(2-naphthyl)propionicacid (0.78 g; 2.39 mmol), 1-hydroxy-7-azabenzotriazole (0.33 g; 2.39mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.55 g; 2.87 mmol) were dissolved in methylene chloride (20 mL) andadded to the reaction mixture. The reaction mixture was stirred for 12hours at room temperature. Methylene chloride (50 mL) was added and thereaction mixture was washed with water (30 mL), an aqueous solution ofsodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodiumhydrogen carbonate/sodium carbonate (pH 9; 30 mL) and water (30 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was chromatographed on silica (2.5×30 cm) using ethylacetate/heptane (2:1) as eluent to afford 0.86 g ofN-((1R)-1-(N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-carbamicacid tert-butylester.

[0496] H-NMR (CDCl₃) (selected peaks, rotamers) d: 1.34 (s, 9H); 2.35(s, 3H); 2.78 (s, 3H); 5.03-5.45 (four m, 2H).

[0497](2R)-N-((1R)-2-(2-Fluorophenyl)-1-methylcarbamoylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide:

[0498]N-((1R)-1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-carbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester (0.85 g; 1.63 mmol) was dissolved in methylenechloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reactionmixture was stirred for 15 min at room temperature. Methylene chloride(25 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 8. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.669 g of(2R)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.

[0499] H-NMR (CDCl₃) (selected peaks, rotamers) d : 2.02 (d, 3H); 2.57(s, 3H); 3.78 (dd, 1H); 5.55 (dd, 1H)

[0500](2-((((1R)-1-(((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)-methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamicAcid Tert-Butyl Ester:

[0501] (2-tert-Butoxycarbonylamino-2-methylpropoxy) acetic acid (0.19 g;0.78 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.12 g; 0.86 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g;0.90 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(0.33 g; 0.78 mmol) and diisopropylethylamine (0.17 mL; 0.86 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (50 mL) was added and the reactionmixture was washed with water (50 mL), an aqueous solution of sodiumhydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogencarbonate (saturated; 50 mL), water (50 mL) and dried (magnesiumsulfate). The solvent was removed in vacuo to afford 0.47 g of

[0502](2-((((1R)-1-(((1R)-2-(2-fluorophenyl)-1-methylcarbamoyl-ethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methyl-carbamoyl)methoxy)-1,1-dimethylethyl)carbamicacid tert-butyl ester.

[0503] H-NMR (CDCl₃) (rotamers, selected peaks for major isomer) d 1.03(s, 3H); 1.06 (s, 3H); 2.78 (s, 3H); 2.80 (d, 3H); 3.98 (s, 3H); 4.95(d, 1H); 5.00 (d, 1H); 5.70 (dd, 1H), 5.85 (dd, 1H).

[0504] (2-((((1R)-1-(((1R)-2-(2-Fluorophenyl)-1(methylcarbamoyl)-ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)-methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamicacid tert-butyl ester (0.46 g; 0.707 mmol) was dissolved in methylenechloride (3 mL). Trifluoroacetic acid (3 mL) was added and the reactionmixture was stirred for 5 min at room temperature. Methylene chloride(25 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 8. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.275 g of thetitle compound.

[0505] H-NMR (CDCl₃) (selected peaks, rotamers) d: 0.76; 0.99 (two d,6H); 2.30; 2.80 (two d, 3H); 2.47; 2.78; 2.94; 2.97 (four s, 6H); (3.90(d), 3.94(s), 4.05 (d), 2H); 5.27; 5.37; 5.67; 5.86 (four dd, 2H);6.96-7.82 (arom. 12H).

[0506] PDMS: m/z 550.7 (M+H)⁺

[0507] HPLC: R_(t)=31.28 min (Method A1)

Example 13

[0508] (2E)-5-Amino-5-methylhex-2-enoic Acid((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide:

[0509](R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionicAcid:

[0510] 2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (5.0g; 17.7 mmol) was dissolved in dry tetrahydrofuran. Iodomethane (8.8 mL;141 mmol) was added and the reaction mixture was cooled to 0° C. Sodiumhydride (2.1 g; 53.0 mmol) was slowly added and the reaction mixture wasstirred for 12 hours at room temperature. Ethyl acetate (50 mL) wasadded and water (20 mL) was added dropwise to the reaction mixture. Theethyl acetate was removed in vacuo and the residue was diluted withdiethyl ether (30 mL) and water (100 mL). The organic phase wasextracted with a saturated aqueous solution of sodium hydrogen carbonate(50 mL). Citric acid (5%) was added to the combined aqueous phases untilpH 3, which were then extracted with ethyl acetate (2×50 mL) and thephases were separated. The organic phase was washed with water (2×50mL), an aqueous solution of sodium thiosulfate (5%; 2×50 mL) and water(50 mL) and dried (magnesium sulfate). The solvent was removed in vacuoand the residue was dissolved in diethyl ether (10 mL).Dicyclohexylamine (10 mL) was added. Methylene chloride (30 mL) wasadded and the mixture was heated until the precipitate was dissolved.Diethyl ether (20 mL) and heptane (20 mL) were added and the reactionmixture was left 12 hours without stirring. The reaction mixture wasfiltered to afford 5.7 g of(R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionicacid as a dicyclohexylammonium salt.

[0511]¹H-NMR (CDCl₃) (mixture of rotamers) d: 1.21; 1.31 (two s, 9H);2.75; 2.84 (two s, 3H); 2.86-3.02 (m, 1H); 3.28-3.42 (m, 1H); 4.65; 4.85(two dd, 1H); 6.85-7.00 (m, 2H); 7.10-7.25 (m, 2H).

[0512] ((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamicAcid Tert-Butylester:

[0513] The dicyclohexylammoniumsalt of(R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionicacid (3.00 g; 10.1 mmol) was dissolved in methylene chloride (30 mL) andwashed with an aqueous solution of sodium hydrogen sulfate (10%; 30 mL).The organic phase was dried (magnesium sulfate) and filtered.1-Hydroxybenzotriazole (1.40 g; 10.1 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.0 g;10.6 mmol) were added to the filtrate and the reaction mixture wasstirred for 15 min at room temperature. Methylamine (40% in methanol;0.75 g; 9.17 mmol) and diisopropylethylamine (1.7 mL; 10.1 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. The reaction mixture was washed with an aqueous solution ofsodium hydrogen carbonate (sat; 50 mL) and an aqueous solution of sodiumhydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). The solventwas removed in vacuo and the residue was chromatographed on silica (3×40cm) using ethyl acetate/heptane (2:1) as eluent to afford 1.06 g of((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acidtert-butylester.

[0514]¹H-NMR (CDCl₃) d: 1.29; 1.37 (two s, 9H); 2.74 (s, 3H); 2.8 (s,3H); 2.82-2.95 (m, 1H); 3.36-3.48 (m, 1H); 4.63; 4.86 (m, 1H); 5.89;6.14 (two s, 1H); 6.9-7.0 (m, 2H); 7.1-7.21 (m, 2H).

[0515] (2R)-3-(4-Fluorophenyl)-N-methyl-2-(methylamino)propion-amide:

[0516] ((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamicacid tert-butylester (1.0 g; 3.22 mmol) was dissolved in methylenechloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reactionmixture was stirred for 30 min at room temperature. Methylene chloride(30 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid), wereadded to the reaction mixture, until pH 9. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.62 g of(2R)-3-(4-fluorophenyl)-N-methyl-2-methylaminopropionamide.

[0517]¹H-NMR (CDCl₃) d: 1.31 (s, 1H); 2.29 (s, 3H); 2.65-2.73 (m, 1H);2.82 (d, 3H); 3.12-3.20 (m, 2H); 6.96-7.02 (m, 2H); 7.11 (s, 1H);7.14-7.20 (m, 2H).

[0518]((1R)-1-(((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)-ethyl)methylcarbamicAcid Tert-Butylester:

[0519] (2R)-2-(tert-Butoxycarbonylmethylamino)-3-(2-naphthyl)propionicacid (1.0 g; 3.1 mmol) was dissolved in methylene chloride (20 mL).1-Hydroxy-7-azabenzotriazole (0.43 g; 3.1 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g;3.3 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0520] (2R)-3-(4-Fluorophenyl)-N-methyl-2-(methylamino)propionamide (0.6g; 2.9 mmol) and diisopropylethylamine (0.54 mL; 3.1 mmol) was added andthe reaction mixture was stirred for 12 hours at room temperature.Methylene chloride (30 mL) was added and the reaction mixture was washedwith water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%;30 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 30 mL) and water (30 mL) and dried (magnesium sulfate).The solvent was removed in vacuo and the residue was chromatographed onsilica (4.0×30 cm) using ethyl acetatelheptane (2:1) as eluent to afford1.07 g of((1R)-1-(((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)-ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamicacid tert-butylester.

[0521]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.34 (s, 9H);2.23 (d, 3H); 2.76 (s, 3H); 2.87 (s, 3H); 5.70 (dd, 1H); 5.95 (dd, 1H).

[0522](2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)-ethyl)-N-methyl-2-methyl-amino-3-(2-naphthyl)propionamide:

[0523]((1R)-1-(((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)-ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamicacid tert-butylester. (1.0 g; 1.92 mmol) was dissolved in methylenechloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reactionmixture was stirred for 15 min at room temperature. Methylene chloride(25 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) was addedto the reaction mixture until pH 8. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.75 g of(2R)-N-((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.

[0524]¹H-NMR (CDCl₃) d: 1.81 (s, 3H); 2.07 (d, 3H); 2.54 (s, 3H);2.68-2.77 (m, 1H); 2.88-2.97 (m, 1H); 3.18 (dd, 1H); 3.27 (dd, 1H); 3.8(dd, 1H); 4.95 (s, 1H); 5.43 (dd, 1H); 6.72 (t, 1H); 6.90 (t, 2H); 7.12(dd, 2H); 7.32 (d, 1H); 7.42-7.50 (m, 2H); 7.62 (s, 1H); 7.70-7.83 (m,2H).

[0525](4(((1R)-1(((1R)-2(4-Fluorophenyl)-1-(methylcarbamoyl)-ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicAcid Tert-Butylester:

[0526] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(0.22 g; 0.89 mmol, prepared as in example 1) was dissolved in methylenechloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2 g;1.02 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0527](2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methyl-amino-3-(2-naphthyl)propionamide(0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature.

[0528] Methylene chloride (50 mL) was added and the reaction mixture waswashed with water (50 mL), an aqueous solution of sodium hydrogensulfate (10%; 50 mL), an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9; 50 mL) and water (50 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (4×30 cm) using ethyl acetate/heptane(2:1) as eluent to afford 0.34 g of(4-(((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)-ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

[0529]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 0.85 (s, 3H);0.87 (s, 3H); 1.42 (s, 9H); 2.12 (d, 3H); 2.72 (s, 3H); 2.96 (s, 3H);5.75 (dd, 1H); 5,92 (dd, 1H); 6.12 (dd, 1H).

[0530](4-(((1R)-1-(((1R)-2-(4-Fluorophenyl)-1-methylcarbamoyl-ethyl)methylcarbamoyl)-2-is(2-naphthyl)ethyl)methyl-carbamoyl)-1,1-:dimethylbut-3-enyl)carbamicacid tert-butylester (0.33 g; 0.51 mmol) was dissolved in methylenechloride (3 mL). Trifluoroacetic acid (3 mL) was added and the reactionmixture was stirred for 5 min at room temperature. Methylene chloride(25 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 9. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.18 g of thetitle compound.

[0531]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.15 (s, 6H);2.14 (d, 3H); 2.73 (s, 3H); 3.09 (s, 3H); 5.23 (dd, 1H); 5.90 (dd, 1H);6.12 (dd, 1H).

[0532] PDMS: m/z 547.4 (M+H)⁺

[0533] HPLC: R_(t)=32.05 min (Method A1)

Example 14

[0534](2R)-2-(((2-Amino-2-methylpropoxy)acetyl)methylamino)-N-((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide:

[0535](2-((((1R)-1-(((1R)-2-(4-Fluorophenyl)-1-methyl-carbamoylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)-methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamicAcid Tert-Butylester:

[0536] (2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.22 g;0.89 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 g;1.02 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) wereadded and the reaction mixture as stirred for 12 hours at roomtemperature. Methylene chloride (50 mL) was added and the reactionmixture was washed with water (50 mL), an aqueous solution of sodiumhydrogen carbonate/sodium carbonate (pH 9; 50 mL), an aqueous solutionof sodium hydrogen sulfate (10%; 50 mL) and water (50 mL) and dried(magnesium sulfate). The solvent was removed in vacuo to afford 0.53 gof(2-((((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-methoxy)-1,1-dimethylethyl)carbamicacid tert-butylester.

[0537]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.20 (s, 3H);1.25 (s, 3H); 1.44 (s, 9H); 2.18 (d, 2H); 2.59 (s, 3H); 2.74 (s, 3H);2.77 (d, 3H); 4.02 (s), 2H); 5.25 (dd, 1H); 5.82 (dd, 1H).

[0538](2-((((1R)-1-(((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)-ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)-methylcarbamoyl)-methoxy)-1,1-dimethylethyl)carbamicacid tert-butylester (0.53 g; 0.81 mmol) was dissolved in methylenechloride (3 mL). Trifluoroacetic acid (3 mL) was added and the reactionmixture was stirred for 5 min at room temperature. Methylene chloride(25 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 25 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 9. The organic phase was dried(magnesium sulfate) and evaporated in vacuo to afford 0.26 g of thetitle compound.

[0539]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d 0.99 (s, 3H);1.09 (s, 3H); 2.25 (d, 3H); 2.28 (s, 3H); 2.95 (s, 3H); 3.90 (s, 2H);5.31 (dd, 1H); 5.83 (dd, 1H).

[0540] PDMS: m/z 550.6 (M+H)⁺

[0541] HPLC: r_(t)=31.83 min (A1)

Example 15

[0542] (2E)-5-Amino-5-methylhex-2-enoic acid((1R)-2-(biphenyl-4-yl)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)methylamide:

[0543](2R)-3-(1,1′-Biphenyl-4-yl)-2-(N-tert-butoxycarbonyl-N-methylamino)propionicAcid:

[0544] 3-(1 ,1′-Biphenyl-4-yl)-2-tert-butoxycarbonylaminopropionic acid(5.0 g; 14.66 mmol) was dissolved in dry tetrahydrofuran (45 mL).Iodomethane (7.3 mL; 117.3 mmol) was added and the reaction mixture wascooled to 00 C. Sodium hydride (1.75 g; 1 544.0 mmol) was added and thereaction mixture was stirred for 5 days at room temperature. Ethylacetate (50 mL) was added and water (20 mL) was added dropwise. Thesolvent was removed in vacuo and the residue was dissolved in an aqueoussolution of sodium hydrogen carbonate (saturated; 50 mL) and washed withdiethyl ether (30 mL). The aqueous phase was acidified to pH 3 usingcitric acid (5%) and extracted with ethyl acetate (3×50 mL). The organicphase was washed with an aqueous solution of sodium thiosulfate (5%; 75mL) and dried (magnesium sulfate). The solvent was removed in vacuo toafford 3.85 g of(2R)-3-(1,1′-biphenyl-4-yl)-2-(N-tert-butoxycarbonyl-N-methylamino)propionicacid.

[0545]¹H NMR (200 MHz, CDCl_(b 3)) d (mixture of rotamers) 1.47 (s,4.5H), 1.49 (s, 4.5H), 2.54 (s, 1.5H, 2.56 (s, 1.5H), 3.00-3.40 (bm,1H), 3.45-3.91 (bm, 1H), 4.53-4.55 (m, 0.5H), 4.55-4.58 (m, 0.5H),7.3-7.6 (m, 9H).

[0546]((1R)-2-(1,1′-Biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)methylcarbamicAcid Tert-Butylester:

[0547](2R)-3-(1,1′-Biphenyl-4-yl)-2-(N-tert-butoxycarbonyl-N-methylamino)propionicacid is (1.50 g; 4.23 mmol) was dissolved in methylene chloride (20 mL).1-Hydroxy-7-azabenzotriazole (0.57 g; 4.23 mmol) andN-(3dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g;4.65 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature. N-Methyl-2-methylamino-3-phenylpropionamide (0.81 g;4.23 mmol) and diisopropylethylamine (0.73 mL; 4.23 mmol) were added andthe reaction mixture was stirred for 12 hours at room temperature.Methylene chloride (50 mL) was added and the reaction mixture was washedwith water (50 mL), an aqueous solution of sodium hydrogen carbonate(sat; 50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50mL) and water (50 mL) and dried (magnesium sulfate). The solvent wasremoved in vacuo and the residue was chromatographed on silica (4×25 cm)using ethyl acetatelheptane (2:1) as eluent to afford 1.02 g of((1R)-2-(1,1′-biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamicacid tert-butyl ester.

[0548]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.15 (s, 6H);1.31 and 1.34 (two s; 9H); 2.24 (d, 3H); 2.80 (s, 3H); 2.98 (s, 3H);4.98 (m, 1H); 5.38 (m, 1H).

[0549] 3-(11′-Biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide:

[0550] ((1R)-2-(1,1′-Biphenyl-4-yl)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)ethyl)methyl-carbamicacid tert-butylester (1.0 g; 1.8 mmol) was dissolved in methylenechloride (4 mL). Trifluoroacetic acid (4 mL) was added and the reactionmixture was stirred for 15 min at room temperature. Methylene chloride(40 mL), an aqueous solution of sodium hydrogen carbonate/sodiumcarbonate (pH 9; 40 mL) and sodium hydrogen carbonate (solid) were addedto the reaction mixture until pH 9. The organic phase was dried(magnesium sulfate) and the solvent was removed in vacuo to afford 0.76g of (2R)-3-(1,1′-biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.

[0551]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.71 (s, 3H);2.58 (s, 3H);

[0552] 2.69 (d, 3H); 5.52 (dd, 2H).

[0553](3E)-4-(((1R)-2-(1,1′-Biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl-carbamoyl)-1,1-dimethylbut-3-enyl)carbamic Acid Tert-Butylester:

[0554] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(0.24 g; 0.98 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2 g;1.02 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-3-(1,1′-Biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide(0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) wereadded and the reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (50 mL) was added and the reactionmixture was washed with water (50 mL), an aqueous solution of sodiumhydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogencarbonate/sodium carbonate (pH 9; 50 mL) and water (50 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (4×20 cm) using ethyl acetate/heptane(2:1) as eluent to afford 0.46 g of ((3E)-4-(((1R)-2-(1,1′-biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)-carbamicacid tert-butylester.

[0555]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.22 (s, 3H);1.23 (s, 3H); 1.42 (s, 9H); 2.75 (d, 3H); 2.82 (s, 3H); 2.98 (s, 3H);5.54 (dd, 1H); 5.82 (dd, 1H); 6.12 (d, J=17 Hz, 1H).

[0556] ((3E)-4-(((1R)-2-(1,′-Biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl-carbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butylester (0.45 g; 0.69 mmol)was dissolved in methylene chloride (10 mL). Trifluoroacetic acid (10mL) was added and the reaction mixture was strirred for 5 min at roomtemperature. Methylene chloride (50 mL), an aqueous solution of sodiumhydrogen carbonate/sodium carbonate (pH 9; 50 mL) and sodium hydrogencarbonate (solid) were added to the reaction mixture until pH 9. Theorganic phase was dried (magnesium sulfate) and evaporated in vacuo toafford 0.22 g of the title compound.

[0557]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.18 (s, 6H);2.75 (d, 3H); 3.5 2.78 (s, 3H); 2.97 (s, 3H); 5.45 (dd, 1H); 5.75 (dd,1H); 6.08 (d, J=17 Hz, 1H).

[0558] ESMS: m/z 555.8 (M+H)⁺

[0559] HPLC: R_(t)=34.45 min (Method A1).

Example 16

[0560] (2E)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0561] ((3E)-1,1,3-Trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic Acid Tert butylester:

[0562] (2E)-5-tertButoxycarbonylamino-3,5-dimethylhex-2enoic acid (0.30g; 1.17 mmol.) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazol (0.16 g; 1 17 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ( 0.26 g;1.28 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.

[0563]N-Methyl-2-methylamino-N-((2R)-1t-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide(0.47 g; 1.67 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropylethylamine (0.20 mL; 1.66 mmol ) was added and thereaction was stirred for 12 hours at room temperature. Methylenechloride (10 mL) was added and the reaction was washed with water (10mL), an aqueous solution of sodium hydrogen sulfate (10%; 10 mL) and anaqueous solution of sodium hydrogen carbonate (pH 8; 10 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (3×30 cm) using ethyl acetate/methylenechloride (1:1) as eluent to afford 0.37 g of((3E)-1,1,3-trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.

[0564]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d 1.1 6 (s, 3H);1.17 (s; 3H); 1.42 (s, 9H); 1.68 (s, 3H); 2.75 (d, 3H); 2.76 (s, 3H);2.95 (s, 3H); 5.21 (dd, 1H); 5.51 (s, 1H); 5.59 (dd, 1H).

[0565]((3E)-1,1,3-Trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester (0.37 g ; 0.56mmol ) was dissolved in methylene chloride (2 mL) and trifluoroaceticacid (2 mL) was added. The reaction mixture was stirred for 5 min atroom temperature. Methylene chloride (2 mL), water (5mL) and sodiumhydrogen carbonate (solid) were added to the reaction until pH=9. Theaqueous phase was extracted with methylene chloride (3×10 mL) and thecombined organic phases were dried (magnesium sulfate). The solvent wasremoved in vacuo to afford 0.17 g of the title compound.

[0566]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d: 1.18 (s, 3H);1.19 (s, 3H); 1.67 (s, 3H); 2.75 (d, 3H); 2.76 (s, 3H); 2.95 (s, 3H);5.52 (dd, 1H); 5.62 (s, 1H); 5.86 (dd, 1H).

[0567] HPLC: R_(t)=31.78 min (Method A1)

[0568] PDMS: m/z 542.8 (M+H)⁺

Example 17

[0569]2-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate:

[0570] Ethyl 2-(tert-butoxycarbonylamino)acetate

[0571] (tert-Butoxycarbonylamino)acetic acid (4.00 g, 22.8 mmol) wasdissolved in dichloromethane (8 ml). Ethanol (1.60 ml, 27.40 mmol) and4-dimethylaminopyridine (0.31 g, 25.1 mmol) were added. The solution wascooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (4.81 g, 25.11 mmol) was added. The solution was stirredfor 16 h, while warming up to room temperature. It was diluted withethyl acetate (150 ml) and 10% aqueous sodium hydrogen sulfate solution(100 ml). The phases were separated. The aqueous phase was extractedwith ethyl acetate (4×50 ml). The combined organic layers were washedwith saturated sodium hydrogen carbonate solution (150 ml) and driedover magnesium sulfate. The solvent was removed in vacuo. The crudeproduct was purified by flash chromatography on silica (100 g), usingethyl acetate/heptane (1:4) as eluent, to give 4.25 g of ethyl2-(tert-butoxycarbonylamino)acetate.

[0572]¹H-NMR (CDCl₃): d 1.30 (t, 3H); 1.47 (s, 9H); 3.90 (d, 2H); 4.21(q, 2H); 5.06 (br, H).

[0573] 2-Hydroxy-2-methylpropylcarbamic Acid Tert-Butyl Ester

[0574] Ethyl 2-(tert-butoxycarbonylamino)acetate (4.17 g, 20.52 mmol)was dissolved in tetrahydrofuran (60 ml). The solution was cooled to−78° C. A 22% solution of methyl magensium chloride intoluene/tetrahydrofuran (purchased from Chemmetallgesellschaft, 27.1 ml,67.72 mmol) was added dropwise. The reaction mixture was stirred for 1.5h at -78° C. and then warmed to room temperature. A 10% aqueous solutionof ammonium chloride (200 ml) was added dropwise. The phases wereseparated. The aqueous phase was extracted with ethyl acetate (3×100ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution (200 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (110 g), using ethyl acetate/heptane(1:1) as eluent, to give 1.31 g of 2-hydroxy-2-methylpropylcarbamic acidtert-butyl ester.

[0575]¹H-NMR (CDCl₃): d 1.21 (s, 6H); 1.45 (s, 9H); 1.34 (d, 2H); 5.00(br, 1H).

[0576] 2-(tert-Butoxycarbonylamino)-1,1-dimethylethyl acetate

[0577] 2-Hydroxy-2-methylpropylcarbamic acid tert-butylester (510 mg,2.69 mmol) was dissolved in dichloromethane (7 ml). The solution wascooled to 0° C. Ethyldiisopropylamine (0.70 ml, 4.04 mmol),4-dimethylaminopyridine (33 mg, 0.27 mmol), and acetic acid anhydride(0.33 ml, 3.50 mmol) were added successively. The reaction mixture wasstirred for 16 h, while slowly warming up to room temperature. It wasdiluted with ethyl acetate (30 ml) and extracted with 1N hydrochloricacid (30 ml). The aqueous phase was extracted with ethyl acetate (2×20ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution (50 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (100 g), using ethyl acetatelheptane(1:2) as eluent, to give 550 mg of2-(tert-butoxycarbonylamino)-1,1-dimethylethyl acetate.

[0578]¹H-NMR (CDCl₃): d 1.45 (s, 9H); 1.46 (s, 6H); 2.00 (s, 3H); 3.35(d, 2H); 4.96 (br, 1H).

[0579] 2-Amino-1,1-dimethylethyl Acetate Hydrochloride

[0580] 2-(tert-Butoxycarbonylamino)-1,1-dimethylethyl acetate (508 mg,2.2 mmol) was dissolved in ethyl acetate (6 ml). 3 M hydrogen chloridein ethyl acetate (4 ml, 12 mmol) was added. The reaction mixture wasstirred for 20 h at room temperature. The precipitation was fillteredoff and washed with diethyl ether (50 ml). It was dried in vacuo to give246 mg of 2-amino-1,1-dimethylethyl acetate hydrochloride.

[0581]¹H-NMR (DMSO d₆): d 1.45 (s, 6H); 2.00 (s, 3H); 3.09 (s, 2H); 8.25(br, 3H).

[0582]2-((2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylAcetate

[0583] (2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionicacid (391 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (6 ml).1-Hydroxybenzotriazole hydrate (189 mg, 1.4 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added.The reaction mixture was stirred for 10 min at room temperature.2-Amino-1,1-dimethylethyl acetate hydrochloride (237 mg, 1.4 mmol) wasadded as a solid. Ethyldiisopropylamine (0.53 ml, 3.1 mmol) was added.The reaction mixture was stirred for 20 h at room temperature. It wasdiluted with ethyl acetate (200 ml) and washed with i N hydrochloricacid. The aqueous phase was extracted with ethyl acetate (2×50 ml). Thecombined organic layers were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (80 g), using ethyl acetate/heptane (1:1) aseluent, to give 442 mg of2-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate.

[0584]¹H-NMR (CDCl₃): d 1.30 and 1.35 (both s, together 6H); 1.41 (s,9H); 1.98 (s, 3H); 2.70-3.05 (m, 4H); 3.30-3.65 (m, 3H); 4.75-4.95 (m,1H); 6.65 (br, 1H); 7.15-7.35 (m, 5H).

[0585] 1,1Dimethyl-2-((2R)-2-methylamino-3-phenylpropionylamino)-ethylAcetate:

[0586]2-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate (426 mg, 1.1 mmol) was dissolved in dichloromethane (2 ml) andcooled to 0° C. Trifluoroacetic acid (2 ml) was added and the reactionmixture was stirred for 15 min at 0° C. The solvent was removed in vacuoat 20° C. The residue was dissolved in dichloromethane (50 ml) and thesolvent was removed in vacuo. This latter procedure was repeated twotimes. The crude product was purified by flash chromatography on silica(45 g), using dichloromethanelmethanol/25% aqueous ammonia (100:10:1) aseluent, to give 312 mg of1,1-dimethyl-2((2R)-2-methylamino-3-phenylpropionylamino)ethyl acetate.

[0587]¹H-NMR (CDCl₃): d 1.43 (s, 6H); 2.00 (s, 3H); 2.30 (s, 3H); 2.67(dd, 1H); 3.24 (m, 2H); 3.53 (ABX, 2H); 7.15-7.45 (m, 5H); 7.61 (br,1H).

[0588]2-((2R)-2-(N-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylAcetate:

[0589](2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (373 mg, 1.13 mmol) was dissolved in N,N-dimethylformamide (2 ml)and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (153 mg, 1.13mmol) was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (217 mg,1.13 mmol) was added. The reaction mixture was stirred for 10 min at 0°C. 1,1-Dimethyl-2-((2R)-2-methylamino-3-phenylpropionylamino)-ethylacetate (301 mg, 1.03 mmol) was dissolved in is dichloromethane (2 ml)and added. Ethyldiisopropylamine (0.18 ml, 1.03 mmol) was added. Thereaction mixture was stirred for 20 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (100 ml) and washed with1 N hydrochloric acid. The aqueous phase was extracted with ethylacetate (3×30 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (85 g), using ethylacetatelheptane (1:1) as eluent, to give 547 mg of2-((2R)-2-(N-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate.

[0590]¹H-NMR (CDCl₃, selected values): d 0.98 and 1.23 (both s, together9H); 1.95 and 2.03 (both s, together 3H); 2.18 and 2.25 (both s,together 3H); 5.05 and 5.35-5.55 (both m, together 2H).

[0591]1,1-Dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propion-yl)amino)-3-phenylpropionylamino)ethylAcetate:

[0592]2-((2R)-2-(N-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate (511 mg, 0.85 mmol) was dissolved in dichloromethane (2 ml) andcooled to 0° C. Trifluoroacetic acid (2 ml) was added, and the solutionwas stirred for 15 min at 0° C. The solvents were removed in vacuowithout warming. The residue was dissolved in dichloromethane (50 ml),and the solvent was removed in vacuo. The latter procedure was repeatedtwo times. The crude product was purified by flash chromatogrpahy onsilica (30 g), using dichloromethane/methanol/25% aqueous ammonia(100:10:1) as eluent, to give 160 mg of 1,1dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenyl-propionylamino)ethylacetate.

[0593]¹H-NMR (CDCl₃, selected values): d 0.82 and 0.90 (s and m,together 6H); 1.86 and 1.91 (both s, together 3H); 2.01 and 2.35 (boths, together 3H); 2.75 and 2.95 (both s, together 3H); 4.60 and 5.50(both dd, together 1H).

[0594]2-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylAcetate:

[0595] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (81mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 ml) anddichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (45 mg, 0.33 mmol)was added. The'solution was cooled to 0 0C.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg,0.36 mmol) was added. A solution of 1,1-dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropionylamino)ethylacetate (152 mg, 0.30 mmol) in dichloromethane (2 ml) andethyldiisopropylamine (0.05 ml, 0.30 mmol) were added successively. Thesolution was stirred for 16 h, while warming up to room temperature. Itwas diluted with ethyl acetate (150 ml), washed with 1N hydrochloricacid (100 ml) and saturated sodium hydrogen carbonate solution, anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (40 g),using ethyl acetate/heptane (first 1:1 (250 ml), then 2:1) to give 221mg of2-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate.

[0596]¹H-NMR (CDCl₃, selected values): d 5.25, 5.45, 5.60, and 5.90 (alldd, together 2 25H); 5.92-6.07 (m, 1H); 6.60-6.85 (m, 1H).

[0597]2-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate (199 mg, 0.27 mmol) was dissolved in dichloromethane (2 ml). Thesolution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. Thesolution was stirred for 15 min at 0° C. The solvent was removed invacuo at 20° C. The residue was dissolved in dichloromethane (50 ml) andthe solvent was removed in vacuo. The latter procedure was repeated twotimes. The crude product was purified by flash chromatography on silica(25 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) aseluent, to give 75 mg of the title compound.

[0598]¹H-NMR (CDCl₃, selected values): d 0.95, 0.96, 0.98, 0.99, 1.16,1.20, 1.35, and 1.40 (all s, together 12H); 1.90 and 1.95 (both s,together 3H); 2.83 and 2.84 (both s, together 3H); 2.98 and 3.03 (boths, together 3H); 5.25, 5.45, 5.57, and 5.90 (all dd, together 2H);6.95-6.1 0 (m, 1H); 6.65-6.90 (m, 1H).

[0599] HPLC: (A1) R_(t)=36.15 min.

[0600] MS: 630±1 [M+1]⁺

Example 18

[0601] (2E)-5-Amino-2-benzyl-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0602] (2E)-2-Benzyl-5-(tert butoxycarbonylamino)-5-methylhex-2-enoicacidmethyl-(1-(methyl-(1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethylamide:

[0603] (2E)-2-Benzyl-5-tert-butoxycarbonylamino-5-methylhex-2-enoic acid(0.125 g 0.38 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.05 g; 0.37 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.08 g;0.41 mmol) were added and the reaction mixture was stirred for 15 min atroom temperature.(2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl))propionamide(0.151 g; 0.37 mmol) is was dissolved in methylene chloride (5 mL) andadded. Diisopropylethylamine (0.064 mL; 0.37 mmol) was added. Thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (5 mL) was added. The reaction mixture was washed with water(10 mL), an aqueous solution of sodium hydrogen sulfate (10%; 10 mL),and an aqueous solution of sodium hydrogen carbonate (pH 8; 10 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was chromatographed on silica (2×20 cm) usingethylacetat/methylene chloride 1:1 as eluent to afford 0.08 g of(2E)-2-Benzyl-5-(tert-butoxy-carbonylamino)-5-methylhex-2-enoicacidmethyl-(1-(methyl-(1-methylcarbamoyl-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethylamide.

[0604]¹H-NMR: (CDCl₃)(selected peaks for major rotamer) d 0.96 (s, 3H);1.11 (s, 3H); 1.38 (s, 9H); 2.65 (d, 3H); 2.71 (s, 3H); 2.99 (s, 3H);4.80 (m, 1H); 5.30 (m, 3H); 5.80 (t, 1H).

[0605] (2E)-2-Benzyl-5-(tert butoxycarbonylamino)-5-methylhex-2-enoicacidmethyl-(1-(methyl-(1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-napthyl)ethylamide (0.10 g; 0.14 mmol) was dissolved in methylene chloride (2 mL) andtrifluoroacetic acid (1 mL) was added. The reaction mixture was stirredfor 5 min at room temperature. Methylene chloride (3 mL) and sodiumhydrogen carbonate (solid) were added until pH 8. The aqueous phase wasextracted with methylene chloride (3×10 mL) and the combined organicphases were dried (magnesium sulfate). The solvent was removed in vacuoto afford 0.09 g of the title compound.

[0606]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 0.89 (s, 3H);0.92 (s, 3H); 2.38 (d, 3H); 2.45 (s, 3H); 2.95 (s, 3H); 5.21 (m, 1H);5.45 (m, 1H).

[0607] ESMS : m/z 618.2 (M+H)⁺

[0608] HPLC: R_(t)=37.53 min (Method A1)

Example 19

[0609] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(1-naphthyl)ethyl)amide:

[0610]Methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamicAcid Tert-Butylester:

[0611] (2R)-2-(tert-Butoxycarbonylmethylamino)-3-(1-naphthyl)-propionicacid (2.00 g; 6.07 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.83 g ; 6.07 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.28 g;6.68 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature. (2R)N-Methyl-2-methylamino-3-phenyl-propionamide (1.17g; 6.07 mmol) was dissolved in methylene chloride (10 mL) and added.Diisopropylethylamine (1.04 mL; 6.07 mmol) was added. The reactionmixture was stirred for 12 hours at room temperature. Methylene chloride(20 mL) was added. The reaction mixture was washed with water (20 mL),an aqueous solution of sodium hydrogen sulfate (10%; 20 mL), and anaqueous solution of sodium hydrogen carbonate (saturated 20 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was chromatographed on silica (3×30 cm) using ethylacetat/methylene chloride 1:1 as eluent to afford 0.77 g ofmethyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamicacid tert-butylester.

[0612]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.39 (s, 9H);2.30 (s, 3H); 2.75 (s, 3H); 3.68 (dd, 1H); 5.35 (dd, 1H).

[0613](2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide:

[0614]Methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamicacid tert butyl ester (0.77 g; 1.52 mmol) was dissolved in methylenechloride (4 mL) and trifluoroacetic acid (4 mL) was added. The reactionmixture was stirred for 30 min at room temperature. Water (5 mL) andmethylene chloride (5 mL) were added. An aqueous solution of sodiumhydrogen carbonate was added until pH 8. The organic phase was extractedwith methylene chloride (3×10 mL) and dried (magnesium sulfate). Thesolvent was removed in vacuo to afford 0.64 g of(2R)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide.

[0615]¹H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1.69 (s, 3H);2.05 (s, 3H); 2.57 (d, 3H); 3.91 (dd, 1H); 5.45 (dd, 1H).

[0616]((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)-ethyl)carbamoyl)but-3-enyl)carbamicAcid Tert Butylester:

[0617] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0. 19g ;0.80 mmol) was dissolved in methylene chloride (1 0 mL).1-Hydroxy-7-azabenzotriazole (0.108 is g; 0.795 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g;0.87 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.(2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3(1-naphthyl)propionamide(0.32 g; 0.80 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropylethylamine (0.14 mL; 0.80 mmol) was added. Thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (5 mL) was added. The reaction mixture was washed with water(30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), anaqueous solution of sodium hydrogen carbonate (saturated; 30 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was chromatographed on silica (3×30 cm) usingethylacetat/methylene chloride 1:1 as eluent to afford 0.26 g of((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert butylester.

[0618]¹H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1.31 (s, 3H);1.32 (s, 3H); 1.48 (s, 9H); 2.45 (d, 3H); 2.65 (s, 3H); 2.92 (s, 3H);5.22 (dd, 1H); 6.03 (dd, 1H); 6.14(d, 1H).

[0619]((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert butylester (0.25 g; 0.40 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reactionmixture was stirred for 5 min at room temperature. Methylene chloride (5mL) and solid sodium hydrogen carbonate were added until pH 8. Thereaction mixture was washed with methylene chloride (3×1 0 mL). Thecombined organic phases were dried (magnesium sulfate) and evaporated invacuo to afford 0.21 g of the title compound.

[0620]¹H-NMR: (CCCl₃) (selected peaks for major rotamer) d 1.22 (s, 3H);1.23 (s, 3H); 2.82 (d, 3H); 2.92 (s, 3H); 3.08 (s, 3H); 5.22 (dd, 1H);5.92 (dd, 1H); 6.12 (d, 1H).

[0621] ESMS: m/z 529.2 (M+H)⁺

[0622] HPLC: R_(t)=30.90 ml (Method A1)

Example 20

[0623](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide:

[0624](1,1-Dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)-ethyl)carbamoyl)methoxy)ethyl)carbamicAcid Tert Butylester:

[0625] (2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.14 g;0.54 mmol)(prepared as in example 33) was dissolved in methylenechloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.54 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were addedand the reaction mixture was stirred for 15 min at room temperature.(2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide (0.21 ; 0.54 mmol) was dissolved in methylene chloride (10mL) and added. The reaction mixture was stirred for 12 hours at roomtemperature. Methylene chloride (10 mL) was added. The reaction mixturewas washed with water (30 mL), an aqueous solution of sodium hydrogensulfate (10%; 20 mL) and an aqueous solution of sodium hydrogencarbonate (saturated; 20 mL) and dried (magnesium sulfate). The solventwas removed in vacuo and the residue was chromatographed on silica (2×20cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford0.27 g of(1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamicacid tert butylester.

[0626]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.39 (s, 3H);1.40 (s, 3H); 1.45 (s, 9H); 2.52 (s, 3H); 2.71 (d, 3H); 2.98 (s, 3H);5.27 (dd, 1H); 5.95 (dd, 1H).

[0627](1,1-Dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)-ethyl)carbamoyl)methoxy)ethyl)carbamicacid tert-butylester (0.26 g; 0.41 mmol) was dissolved in methylenechloride (3 mL) is and trifluoroacetic acid (2 mL) was added. Thereaction mixture was stirred for 5 min at room temperature. Methylenechloride (5 mL), an aqueous solution of sodium hydrogen carbonate(saturated) and sodium hydrogen carbonate (solid) were added until pH 8.The aqueous phase was extrated with methylene chloride (3×15 mL) and thecombined organic layers were dried (magnesium sulfate). The solvent wasremoved in vacuo to afford 0.25 g of the title compound.

[0628]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.18 (s, 3H);1.23 (s, 3H); 2.48 (s, 3H); 2.53 (s, 3H); 2.99 (s, 3H); 4.54 (dd, 1H);5.25 (dd, 1H).

[0629] ESMS: m/z 533.2 (M+H)⁺

[0630] HPLC: R_(t)=30.68 min (Method A1)

Example 21

[0631] (2E)-5-Amino-5-methylhex-2-enoicAcid-((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)-methylamide:

[0632](2R)-3-(Benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonylmethylamino)propionicAcid

[0633](2R)-3-(Benzo[b]thiophen-3-yl)-2-tert-butoxycarbonylamino-propionic acid(2.65 g; 8.25 mmol) was dissolved in dry tetrahydrofuran. Methyl iodidewas added and the reaction mixture was cooled to 0° C. Sodium hydride(60% in mineral oil, 0.80 g, 24.8 mmol) was added. The reaction mixturewas stirred for 48 hours at room temperature. Ethyl acetate (25 mL) andwater (10 mL) were added dropwise. The solvent was removed in vacuo andthe residue was dissolved in ether (15 mL) and water (15 mL). Theorganic phase was washed with an aqueous solution of sodium hydrogencarbonate (saturated; 20 mL). To the aqueous phase was added citric acid(5%) until pH 3 and extracted with ethyl acetate (4×20 mL). The combinedis organic phases were washed with water (2×30 mL), an aqueous solutionof sodium thiosulfate (5%; 30 mL) and water (30 mL) and dried (magnesiumsulfate). The solvent was removed in vacuo and the residue was dissolvedin ether (10 mL). Dicyclohexylamine (5 mL) was added. The precipitatedcrystals were filtered off, washed with ether (2×10 mL) and dissolved inwater (30 mL). An aqueous solution of sodium hydrogen sulfate (10%; 20mL) and ethyl acetate (40 mL) were added. The aqueous phase was extratedwith ethylacetate (4×30 mL) and dried (magnesium sulfate). The solventwas removed in vacuo to afford 3.75 g of(2R)-3-(benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonylmethylamino)propionic acid.

[0634]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.45 (s, 9H);2.81 (s, 3H); 3.21-3.61 (m, 2H); 4.88 (dd, 1H); 7.18 (s, 1H).

[0635]((1R)-2-(Benzo[b]thiophen-3-yl)-(methyl-((1R)-1-methylcarbamoyl-2-phenyl-ethyl)carbamoyl)ethyl)methylcarbamicAcid tert butylester:

[0636] (2R)-3-(Benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonylmethylamino)propionic acid (2.00 g ; 5.96 mmol) was dissolved inmethylene chloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.81 g; 5.96mmol) and N-(3-dimethylaminopropyl)-N ethylcarbodiimide hydrochloride(1.26 g ; 6.56 mmol) were added. The reaction mixture was stirred for 15min at room temperature.(2R)-N-Methyl-2-methylamino-3-phenylpropionamide (1.15 g; 5.96 mmol) wasdissolved in methylene chloride (1 0 mL) and added.Diisopropylethylamine (1.02 mL; 5.96 mmol) were added. The reactionmixture was stirred for 48 hours. Methylene chloride (10 mL) was added.The reaction was washed with water (30 mL), an aqueous solution ofsodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodiumhydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). Thesolvent was removed in vacuo and the residue was chromatographed onsilica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluentto afford 0.89 g of((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamic acid tert-butylester.

[0637]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.43 (s, 9H);2.26 (d, 3H); 2.75 (s, 3H); 2.76 (s, 3H); 4.96 (dd, 1H); 5.05 (dd, 1H).

[0638](2R)-3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide:

[0639]((1R)-2-(Benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenyl-ethyl)carbamoyl)ethyl)-methylcarbamicacid tert-butylester (0.89 g; 1.70 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reactionmixture was stirred for 45 min at room temperature. Water (5 mL) wasadded. Methylene chloride (5 mL), an aqueous solution of sodium hydrogencarbonate (saturated) and sodium hydrogen carbonate (solid) was addeduntil pH 8. The aqueous phase was extracted with methylene chloride(3×10 mL). The combined organic phases were dried (magnesium sulfate)and evaporated in vacuo to afford 0.66 g of(2R)-3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.

[0640]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.71 (s, 3H);2.38 (s, 3H); 2.62 (d, 3H); 3.82 (dd, 1H); 5.47 (dd, 1H).

[0641](3E)-4-(((1R)-2-(Benzo[b]thiophen-3-yl)-1-(methyl-(1-methylcarbamoyl-2-phenyl-ethyl)carbamoyl)ethyl)-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicAcid Tert-Butylester:

[0642] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(0;19 g; 0.78 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.11 g; 0.78 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.16 g; 0.86 mmol) wereadded. The reaction mixture was stirred for 15 min at room temperature.3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide(0.32 g ; 0.78 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropylethylamine (0.13 mL; 0.78 mmol) was added. Thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (10 mL) was added. The reaction was washed with water (20 mL),an aqueous solution of sodium hydrogen sulfate (10%; 20 mL), an aqueoussolution of sodium hydrogen carbonate (saturated; 20 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (2×20 cm) using ethylacatate/methylenechloride (1:1) as eluent to afford 0.26 g of((3E)-4-(((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-(1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butylester.

[0643]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 3H);1.27 (s, 3H); 1.38 (s, 9H); 2.47 (s, 3H); 2.72 (d, 3H); 2.98 (s, 3H);5.06 (dd, 1H); 5.67 (dd, 1H); 6.08 (d, 1H).

[0644]((3E)-4-(((1R)-2-(Benzo[b]thiophen-3-yl)-1-(methyl-(1-methylcarbamoyl-2-phenyl-ethyl)carbamoyl)ethyl)-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butylester was dissolved in methylene chloride (3 mL) andtrifluoroacetic acid (2 mL) was added. The reaction mixture was stirredfor 5 min at room temperature. Water (5 mL) was added. Methylenechloride (8 mL), an aqueous solution of sodium hydrogen carbonate(saturated), sodium hydrogen carbonate (solid) was added until pH 8. Theaqueous phase was extracted with methylene chloride (3×10 mL) and thecombined organic phases were dried (magnesium sulfate). The solvent wasremoved in vacuo to give 0.13 g of the title compound.

[0645]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 6H);2.47, (s, 3H); 2.75 (d, 3H); 2.96 (s, 3H); 4.98 (dd, 1H); 5.89 (dd, 1H);6.10 (d, 1H).

[0646] PDMS: m/z 535.7 (M+H)⁺

[0647] HPLC: R_(t)=30.87 min (Method A1)

Example 22

[0648](2R)-2-(((2-Amino-2-methylpropoxy)acetyl)methyl-amino)-3-(benzo[b]thiophen-3-yl)-N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide:

[0649](2-((((1R)-2-(Benzo[b]thiophen-3-yl)-((methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamoyl)methoxy)-1,1-dimethylethyl)-carbamic Acid Tert Butyl Ester:

[0650] (2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.193 9g0.78 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.11 g; 0.78 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g;0.86 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.(2R)-3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide(0.32 g ; 0.78 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropylethylamine (0.13 mL; 0.78 mmol) was added. Thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (10 mL) was added. The reaction was washed with water (30 mL),an aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and anaqueous solution of sodium hydrogen carbonate (saturated; 20 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and theresidue was chromatographed on silica (3×30 cm) using ethylacetate/methylene chloride (1:1) as eluent to afford 0.44 g of(2-((((1R)-2-(benzo[b]thiophen-3-yl)-1-((methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-ethyl)methylcarbamoyl)methoxy)-1,1-dimethylethyl)carbamic acid tert butyl ester.

[0651]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 3H);1.28 (s, 3H); 1.42 (s, 9H); 2.70 (s, 3H); 2.78 (d, 3H); 2.97 (s, 3H);4.99 (dd, 1H); 5.88 (dd, 1H).

[0652](2-((((1R)-2-(Benzo[b]thiophen-3-yl)-1-((methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl-carbamoyl)methoxy)-1,1-dimethylethyl)-carbamicacid tert butyl ester (0.435 g; 0.68 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reactionmixture was stirred for 5 min at room temperature. Water (5 mL) wasadded. Methylene chloride (8 mL), an aqueous solution of sodium hydrogencarbonate (saturated) and solid sodium hydrogen carbonate was addeduntil pH 8. The aqueous phase was washed with methylene chloride (3×10mL). The combined organic phases were dried (magnesium sulfate) andevaporated in vacuo to afford 0.36 g of the title compound.

[0653]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 6H);2.65 (s, 3H); 2.75 (s, 3H); 2.98 (s, 3H); 4.68 (dd, 1H); 5.79 (dd, 1H).

[0654] HPLC: R_(t)=30.35 min (Method A1)

[0655] PDMS : m/z 538.1 (M+H)⁺

Example 23

[0656] (2E)-5-Amino-5-methylhex-2-enoic Acidmethyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)-methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)-amide:

[0657] (2R)-2-(tert-Butoxycarbonylmethylamino)-3(1-naphthyl)-propionicAcid:

[0658] 2-tert-Butoxycarbonylamino-3-(1-naphthyl)propionic acid (5.0 g;0.015 mol) was dissolved in tetrahydrofuran (40 mL). Iodomethane (7.6mL; 0.12 mol) was added. The reaction mixture was cooled to 0° C. andsodium hydride was added. The reaction mixture was stirred for 48 hours.Ethyl acetate (50 mL) and water (20 mL) were added dropwise. The solventwas removed in vacuo and ether (30 mL) and water (20 mL) were added. Theorganic phase was washed with an aqueous solution of sodium hydrogencarbonate (pH 8 ; 30 mL). To the aqueous phases was added citric acid(5%) to pH 3. The aqueous phase was extrated with ethylacetate (3×30mL). The combined organic phases were washed with water (2×40 mL), anaqueous solution of sodiumthiosulfate (5%; 40 mL) and water (40 mL) anddried (magnesium sulfate). The solvent was removed in vacuo and ether(10 mL) and dicyclohexylamine (8.5 mL) were added. The precipitatedcrystals were filtered off and dissolved in water (20 mL). Hydrochloricacid was added to pH 2. The reaction mixture was extrated with ethylacetate (4×40 mL), dried (magnesium sulfate) and evaporated in vacuo toafford 3.97 g of (2R)-2-(tert-butoxycarbonylmethylamino)-3-(1-naphthyl)propionic acid.

[0659]¹H-NMR: (CDCl₃) d 1.01 (s, 9H); 2.76 (s, 3H); 3.32 (dd, 1H); 3.93(dd, 1H); 4.95 (dd, 1H); 7.30-8.10 (7 arom. H)

[0660]Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)-methyl)-carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamicAcid Tert-Butylester:

[0661] (2R)-2-(tert-Butoxycarbonylmethylamino)-3-(1-naphthyl)-propionicacid (0.68 g; 2.06 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazol (0.28 g; 2.06 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.43 g;2.26 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.

[0662](2R)-2-Methylamino-3-phenyl-N-((2-tetrahydrofuranyl)-methyl)propionamide(0.54 g; 2.058 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropylethylamine (0.35 mL; 2.06 mmol) was added and thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (10 mL) was added. The reaction mixture was washed with water(30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), anaqueous solution of sodium hydrogen carbonate (pH 8; 30 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (5×50 cm) using ethyl acetate/methylenechloride 1:1 as eluent to afford 1.08 g ofmethyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamicacid tert butylester.

[0663]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 0.71 (s, 9H);1.64 (s, 3H); 2.25 (s, 3H); 2.83 (d, 2H); 2.85 (s, 3H); 5.15 (dd, 1H);5.44 (dd, 1H).

[0664](2R)-N-Methyl-2-methylamino-3-(1-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide:

[0665]Methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphtyl)ethyl)carbamicacid tert butylester (0.84 g; 1.46 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reactionmixture was stirred for 5 min at roomtemperature. Water (3 mL) andmethylene chloride (5 mL) was added. Sodium hydrogen carbonate (solid)was added until pH 8. The reaction mixture was extracted with methylenechloride (3×10 mL). The combined organic layers were dried (magnesiumsulfate) and evaporated in vacuo to afford 0.68 9 of(2R)-N-methyl-2-methylamino-3-(1-naphtyl)-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-yl-methyl)-carbamoyl)ethyl)propionamide.

[0666]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.75 (s, 3H);2.08 (s, 3H); 2.40 (d, 2H); 2.95 (d, 3H); 4.45 (m, 1H); 5.45-5.50 (m,2H).

[0667] ((3E)-1,1-Dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-carbamoyl)-2(1-naphtyl)ethyl)carbamoyl)but-3-enyl)carbamicAcid Tert Butylester:

[0668] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (0.344g; 1.41 mmol) was dissolved in methylene chloride (10 mL).1-Hydroxy-7-azabenzotriazole (0.19 g; 1.41 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.298 g;1.56 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.(2R)-N-Methyl-2-methylamino-3-(1-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-propionamide(0.67 g; 1.42 mmol) was dissolved in methylene chloride (10 mL) andadded. Diisopropyletylamine (0.242 mL; 1.41 mmol) was added. Thereaction mixture was stirred for 12 hours at room temperature. Methylenechloride (20 mL) was added. The reaction mixture was washed with water(30 mL), an aqueous solution of sodium hydrogen sulfate (10%;30 mL), anaqueous solution of sodium hydrogen carbonate (pH 8; 30 mL) and dried(magnesium sulfate). The solvent was removed in vacuo and the residuewas chromatographed on silica (3×30 cm) using methylene chloride/ethylacetat (1:1) as eluent to afford 0.81 g of((3E)-1,1-dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2(1-naphtyl)ethyl)-carbamoyl)but-3-enyl)carbamicacid tert butylester.

[0669]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.28 (s, 9H);1.47 (s, 6H); 2.90 (d, 3H); 6.06 (d, 1H).

[0670]((3E)-1,1-Dimethyl-4-(methyl-((1R)-1-(methyl-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)-carbamoyl)-2(1-naphtyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert butylester (0.80 g; 1.15 mmol) was dissolved in methylenechloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reactionmixture was stirred for 5 min at room temperature. Methylene chloride (5mL) and sodium hydrogen carbonate were added until pH 8. The reactionmixture was extracted with methylene chloride (3×10 mL). The combindorganic phases were dried (magnesium sulfate) and evaporated in vacuo toafford 0.50 g of the title compound.

[0671]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 6H);2.25 (d, 2H); 2.08 (s, 3H); 2.89 (d, 3H); 3.18 (s, 3H); 5.90 (dd, 1H);6.65 (d, 1H).

[0672] PDMS: m/z 599.8 (M+H)⁺

[0673] HPLC: R_(t)=33.50 (Method A1)

Example 24

[0674]3-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylAcetate:

[0675]N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methylcarbamicAcid Tert-Butylester:

[0676] 3-Aminopropan-1-ol (0.39 mL, 5.12 mmol) was added at roomtemperature to a solution ofN-tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.30 g, 4.65 mmol) inN,N-dimethylformamide (40 mL). 1-Hydroxybenzotriazole monohydrate (0.63g, 4.65 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.89 g, 4.65 mmol) were added successively. The reactionmixture was stirred for 22 h at room temperature. It was diluted with 10% sodium hydrogensulfate solution (300 mL) and extracted with ethylacetate (4×100 mL). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo and the crudeproduct was purified by flash chromatography on silica (45 g) withdichloromethane/methanol (10:1) to give 1.01 g ofN-((1R)-1-(3-hydroxypropylcarbamoyl)-2phenylethyl)-N-methylcarbamic acidtert-butylester.

[0677]¹H-NMR (CDCl₃): d 1.30 and 1.40 (both s, together 9H); 1.65 and1.72 (both br, together 2H); 2.77 (s, 3H); 2.90-3.75 (m, 6H); 4.75 and4.86 (both m, together 1H); 6.50 (m, 1H); 7.10-7.25 (m, 5H).

[0678]3-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propylAcetate:

[0679] A solution ofN-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methyl-carbamicacid tert-butylester (965 mg, 2.86 mmol) in dichloromethane (10 mL) wascooled to 0° C. 4-(dimethylamino)pyridine (35 mg, 0.29 mmol),triethylamine (0.60 mL, 4.29 mmol), and acetic acid anhydride (0.32 mL,3.43 mmol) were added. The reaction mixture was stirred for 5 hours,while it was warming slowly to room temperature. The reaction mixturewas diluted with dichloromethane (100 mL) and washed with 10% sodiumhydrogensulfate solution. The aqueous phase was extracted withdichloromethane (2×50 mL). The organic phases were combined and washedwith saturated sodium hydrogen carbonate solution. They were dried overmagnesium sulfate. The solvent was removed in vacuo, and the crudeproduct was purified by flash chromatography on silica (90 9) with ethylacetate/dichloromethane (1:3 to 1:1) to give 890 mg of3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propylacetate.

[0680]¹H-NMR (CDCl₃) d 1.25 and 1.39 (both s, together 9H); 1.85 (m,2H); 2.06 and 2.07 (both s, together 3H); 2.76 (s, 3H); 2.95 (m, 1H);3.35 (m, 3H); 4.00-4.20 (m, 2H); 4.70-4.87 (both m, together 1H); 6.22and 6.37 (both br, together 1H); 7.10-7.35 (m, 5H).

[0681] 3-((2R)-2-(Methylamino)-3-phenylpropionylamino)propyl Acetate:

[0682] A solution of3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenyl-propionylamino)propylacetate (862 mg, 2.28 mmol) in dichloromethane (3 mL) was cooled to 0°C. Trifluoroacetic acid (3 mL) was added. The solution was stirred for10 min. The solvents were removed in vacuo without warming. The residuewas dissolved in dichloromethane (50 mL) and the solvent was removed invacuo. The procedure was repeated twice. The crude product was purifiedby flash chromatography on silica (70 g) withdichloromethane/methanol/25% ammonia in water (100:10:1) to give 602 mgof 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propyl acetate.

[0683]¹H-NMR (CDCl₃) d 1.85 (m, 2H); 2.07 (s, 3H); 2.80 (s, 3H); 2.72(dd, 1H); 3.20 (m, 2H); 3.35 (m, 2H); 4.10 (t, 1H); 7.15-7.40 (m, 6H).

[0684]3-((2R)-2-(N-((2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylAcetate:

[0685]2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionicacid (659 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (3 mL)and dichloromethane (3 mL). The solution was cooled to 0° C.1-Hydroxy-7-azabenzotriazole (272 mg, 2.0 mmol) was added. After 10 minN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg,2.4 mmol) was added. The reaction mixture was stirred for 10 min. Asolution of 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propylacetate (567 mg, 2.0 mmol) in dichloromethane (4 mL) was added. Thesolution was stirred for 16 hours, while the temperature rose to roomtemperature. The reaction mixture was diluted with ethyl acetate (150mL). It was extracted with 10% sodium hydrogensulfate solution (150 mL).The aqueous phase was extracted with ethyl acetate (3×50 mL) and theorganic phases were combined and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (70 g) with ethyl acetatelheptane (2:1) to give973 mg of3-(2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate.

[0686]¹H-NMR (CDCl₃): d 4.99, 5.11, 5.18, 5.35, and 5.42 (all dd,together 2H); 5.75 and 6.15 (both t, together 1H).

[0687]3-((2R)-2-(N-((2R)-2-Methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylAcetate:

[0688] At 0° C., trifluoroacetic acid (3 mL) was added to a solution of3-((2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate (885 mg, 1.50 mmol) in dichloromethane (3 mL). The reactionmixture was stirred for 5 min. The solvents were removed in vacuo at 20°C. The residue was dissolved in dichloromethane (40 mL). The S procedurewas repeated twice. The crude product was purified by flashchromatography on silica (45 g) with dichloromethanelmethanol/25%solution of ammonia in water (100:10:1) to give 497 mg of3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate.

[0689]¹H-NMR (DMSO-d₆): d 1.65 (m, 2H); 2.01 and 2.02 (both s, together3H); 4.67 and 5.35 (both dd, together 1H).

[0690]3-((2R)-2-(N-((2R)-2-(N-((2E)-5-tert-Butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenyl-propionylamino)propylAcetate:

[0691] (2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (277 mg,1.14 mmol) and 1-hydroxy-7-azabenzotriazole (155 mg, 1,14 mmol) weredissolved in dichloromethane (3 mL) and N,N-dimethylformamide (3 mL).The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (254 mg,1.32 mmol) was added. The solution for stirred for 10 min at 0° C.,before a solution of3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate in dichloromethane (3 mL) was added. The solution was stirredfor 18 hours, while it was warming up slowly to room temperature. It wasdiluted with ethyl acetate (100 mL) and extracted with 10% sodiumhydrogensulfate solution. The aqueous phase was extracted with ethylacetate (2×50 mL). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 mL) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatogrpahy on silica (45 g) with ethylacetate/heptane (2:1) to give 427 mg of3-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate.

[0692]¹H-NMR (CDCl₃): d 1.80 (m, 2H); 4.10 (m, 2H); 6.05 (m, 1H); 6.75(m, 1H).N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenyl-propionylamino)propylacetate (412 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL). Thesolution was cooled to 0° C. Trifluoroacetic acid (2 mL) was added. Thesolution was stirred for 8 min at 0° C., and the solvents were removedin vacuo with a water bath temperature of 20° C. The residue wasdissolved in dichloromethane (30 mL) and the solvent was removed invacuo. This latter procedure was repeated twice. The crude product waspurified by flash chromatography on silica (35 g) withdichloromethanelmethanol/25% ammonia in water (100: 10:1). The productwas dissolved in ethyl acetate (3 mL) and 3M hydrogen chloride in ethylacetate (0.7 mL) was added. The solvent was removed in vacuo and theproduct was dried over night in vacuo to give 0.21 g of title compoundas a hydrochloride.

[0693]¹H-NMR (DMSO-d₆) (selected values) d 1.70 (m, 2H); 4.00 (m, 2H).

[0694] MS: found: 616.3±1 [M+1]⁺

[0695] HPLC: R_(T)=20.47 min (method A1)

Example 25

[0696] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(3-hydroxypropyl-carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-amide:

[0697]3-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-anphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate hydrochloride (140 mg, 0.21 mmol) was dissolved in 1,4-dioxane(3 mL). A solution of lithium hydroxide (18 mg, 0.74 mmol) in water (1.5mL) was added. Water was added until a clear solution was obtained. Thereaction mixture was stirred for 16 h at room temp. It was diluted withwater (30 mL) and extracted with tert-butylmethyl ether. The combinedorganic layers were dried over magnesium sulfate and the solvent wasremoved in vacuo. The residue was dissolved in water (15 mL) and aceticacid (0.8 mL) and the resulting solution was lyophilized to give 105 mgof the acetate salt of the title compound.

[0698]¹H-NMR (DMSO-d₆) (selected peaks): d 0.95 (s, 6H); 1.55 (m, 3H);3.42 (m, 2H).

[0699] HPLC: R_(T)=30.97 min (method A1)

Example 26

[0700] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0701] (2R)-2-(Methylamino)-3-phenylpropan-1-ol:

[0702] (2R)-2-(Methylamino)-3-phenylpropan-1-ol was prepared analogue toM. J. McKennon and A. I. Meyers J. Org. Chem. 1993 (58), 3568-3571. m.p.69-69° C. (lit: A. I. Meyers, J. Org. Chem. 1993 (58), 3568-3571: 71-74°C.; A. Karim, A. Mortreux, F. Petit, G. Buono, G. Pfeiffer, C. Siv, J.Organomet. Chem. 1986, 317, 93: 68° C., for(2S)-2-(methylamino)-3-phenylpropan-1-ol)

[0703] N-((1R)-1-Hydroxymethyl-2-phenylethyl)-N-methyl carbamaic AcidTert-Butylester:

[0704] (2R)-2-(Methylamino)-3-phenylpropan-1-ol (6.00 g, 36.3 mmol) wasdissolved in Tetrahydrofuran (80 mL). 1N sodium hydroxide solution (36.3mL, 36.3 mmol) was added. A solution of di-tert.-butyl dicarbonate (9.50g, 43.6 mmol) in tetrahydrofuran (60 mL) was slowly added at roomtemperature. The solution was stirred 16 h at room temperature. Water(200 mL) and ethyl acetate (200 mL) were added. The phases wereseparated. The aqueous phase was washed with ethyl acetate (2×100 mL).The combined organic phases were dried over magnesium sulfate. Thesolvent was removed in vacuum. The product was purified on silica (170g) with ethyl aceate/heptane (1:1) to give 7.85 g (81%) ofN-((1R)-1-hydroxymethyl-2-phenylethyl)-N-methyl carbamaic acidtert-butylester.

[0705]¹ H-NMR (CDCl₃): d =1.32-1.40 (br, 9H); 2.55-2.95 (m, 5H);3.65-3.67 (br, 2H); 4.10-4.35 (br, 1H); 7.05-7.35 (m, 5H).

[0706] ((2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropoxyl)aceticAcid Ethyl Ester:

[0707] N-((1R)-1-Hydroxymethyl-2-phenylethyl)-N-methyl carbamaic acid(3.98 g, 15.0 mmol) was dissolved in 1,2-dichloroethane (150 mL). Thesolution was warmed to 75-80° C. Rhodium(II) acetate (0.1 g, 0.4 mmol)was added. During a period of 6 hours a solution of ethyl diazoacetate(2.4 mL, 22.5 mmol) in dichloromethane (100 mL) was added. After 3 hanother portion of rhodium(II) acetate (0.1 g, 0.4 mmol) was added.After addition of ethyl diazoacetate, the solution was cooled to roomtemperature. It was filtered through a plug of celite. The solvent wasremoved in vacuum. The crude product was chromatographed on silica(100g) to give 1.53 g of((2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropoxyl)acetic acidethyl ester.

[0708] 1H-NMR (CDCl₃): d=1.28 (m, 3H); 1.39 and 1.48 (both s, together9H); 2.65-2.95 (m, 9H); 3.58 (m, 1H); 3.67 (br, 1H); 3.98-4.27 (m, 4H);4.35-4.55 (br, 1H); 7.10 -7.30 (m, 5H).

[0709] ((2R)-2-(tert-Butoxycarbonylmethylamino)-3-phenylpropoxy)-aceticacid:

[0710] ((2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropoxyl)-aceticacid ethyl ester (0.60 g, 1.71 mmol) was dissolved in dioxane (5 mL). Asolution of lithium hydroxide (0.05g, 2.20 mmol) in water (2 mL) wasadded. The solution was stirred at room temperature for 56 hours. Ethylacetate (10 mL) and water (2 mL) were added. The phases were separated.The aqueous phase was extracted with ethyl acetate (10 mL). The combinedorganic layers were extracted with 1N sodium hydroxide solution (20 mL).The combined aqueous phases were acidified with a 1M sodiumhydrogensulfate solution (pH 2) and extracted with ethyl acetate (2×20mL). These ethyl acetate layers were combined and dried over magnesiumsulfate. The solvent was removed in vacuum to give 0.38 g of crude((2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropoxy) acetic acid,which was used for the following steps.

[0711] 1H-NMR (DMSO d₆): d=1.15 and 1.27 (both s, together 9H);2.55-2.70 (m, 5H); 3.45-3.65 (m, 2H); 4.00-4.10 (m, 2H); 4.30-4.50 (m,1H); 7.15-7.35 (m, 5H); 13.60 (br, 1H).

[0712]N-Methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl-2-phenyl-ethyl)carbamicAcid Tert-Butylester:

[0713] At −13° C., isobutyl chloroformate (0.80 mL, 6.19 mmol) was addedslowly to a acid (2.0 g, 6.18 mmol) and N-methylmorpholine (0.68 mL,6.18 mmol) in f tetrahydrofuran (25 mL). The solution was stirred for 15min at this temperature. Acetamidoxim (0.92 g, 12.36 mmol) was added asa solid. Immediately after addition, N-methylmorpholine (0.68 mL, 6.18mmol) was given to the reaction mixture. It was stirred for 45 min at−13° C., 3.5 h at room temperature and 16 hours at reflux. The reactionmixture was cooled to room temperature and diluted with ethyl acetate(100 mL). It was extracted with water and 10% sodium hydrogensulfatesolution (10 mU 40 mL). The aqueous phase was extracted with ethylacetate (2×50 mL). The combined organic phases were washed withsaturated sodium hydrogen carbonate solution and dried over magnesiumsulfate. The solvent was removed in vacuo. The crued product waspurified on silica (90 g) with ethyl acetate/heptane (1:1) as eluent togive 1.17 g ofN-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl-2-phenylethyl)carbamcicacid tert-butylester.

[0714]¹H-NMR (CDCl₃) d 1.31 and 1.39 (both s, together 9H); 2.43 (s,3H); 2.65-2.95 (m, 5H); 3.65 (m, 1H); 3.76 (m, 1H); 4.43 and 4.53 (bothbr, together 1H); 4.70-4.80 (m, 2H); 7.10-7.35 (m, 5H).

[0715]3-Methyl-5-(((2R)-2-(methylamino)-3-phenylpropoxy)methyl)-1,2,4-oxadiazole:

[0716]N-Methyl-N-((1R)-1-(((3-methyl-,2,4-oxadiazol-5-yl)methoxy)methyl-2-phenyl-ethyl)carbamcicacid tert-butylester (1.13 g; 3.13 mmol) was dissolved indichloromethane (3 mL). The solution was cooled to 0° C. Trifluoroaceticacid (3 mL) was added. The solution was stirred at 0° C. for 5 min. Thesolvent was removed in vacuo without warming. The residue was dissolvedin dichloromethane (100 mL) and the solvent was removed in vacuo. Thisprocedure was repeated twice. The crude product was purified by flashchromatography on silica (70 g) with dichloromethane/methanol/25%aqueous ammonia (100:10:1) to give 0.75 g of3-methyl-5-(((2R)-2-(methylamino)-3-phenylpropoxy)methyl)-1,2,4-oxadiazole.

[0717]¹H-NMR (CDCl₃) d 2.40 (s, 3H); 2.45 (s, 3H); 2.75 (dd, 1H); 2.85(dd, 2H); 2.93 (m, 1H); 3.48 (dd, 1H); 3.56 (dd, 1H); 4.70 (AB, 2H);7.15-7.35 (m, 5H)).

[0718]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicAcid Tert-Butylester:

[0719](2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionicacid (701 mg, 2.68 mmol) was dissolved in dichloromethane (4 mL) andN,N-dimethylformamide (4 mL). The solution was cooled to 0° C.1-Hydroxy-7-azabenzotriazole (365 mg, 2.68 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (617 mg, 3.22mmol) were successively added. The solution was stirred for 15 min at 0°C. A solution of3-methyl-5-(((2R)-2-(methylamino)-3-phenylpropoxy)methyl)-1,2,4-oxadiazole(701 mg, 2.68 mmol) in dichloromethane (4 mL) was added. The reactionmixture was stirred for 16 hours, while the temperature slowly rose toroom temperature. It was diluted with ethyl acetate (100 mL) andextracted with a mixture of saturated sodium chloride solution (50 mL)and water (50 mL). The aqueous phase was extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution and dried over magensium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (90 g) with ethyl acetate/heptane (2:1) to give1.23 g ofN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butylester.

[0720]¹H-NMR (CDCl₃) d 0.95, 1.02, 1.13, and 1.26 (all s, together 9H);2.35-2.45 (m, 3H); 7.00-7.80 (m, 12H).

[0721] (2R)-2-(Methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)amide:

[0722]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)-methoxy)methyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butylester (1.21 g, 2.12 mmol) was dissolved indichloromethane (4 mL). The solution was cooled to 0° C. Trifluoroaceticacid (4 mL) was added. The solution was stirred for 12 min at 0° C. Thesolvent was removed in vacuo without warming. The residue was dissolvedin dichloromethane (150 mL), and the solvent was removed in vacuo. Thislatter procedure was repeated twice. The crude product was purified byflash chromatogrpahy on silica (70 g) with dichloromethane/methanol/25%aqueous ammonia (200:10:1) to give 497 mg of(2R)-2-(methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxaidazol-5-yl)methoxy)methyl)-2-phenylethyl)amide.

[0723]¹H-NMR (DMSO d₆) d 1.67 and 1.92 (both s, together 3H); 2.32 and2.34 (both s, together 3H); 2.71 and 2.86 (both s, together 3H); 4.60and 4.79 (both s, together H); 7.05-7.90 (m, 12H).

[0724](3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadizol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)-carbamoyl)but-3-enylcarbamicAcid Tert-Butylester:

[0725] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (258mg, 1.06 mmol) was dissolved in dichloromethane (3 mL) andN,N-dimethylformamide (3 mL). 1-Hydroxy-7-azabenzotriazole (144 mg, 1.06mmol) was added. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (260 mg,1.36 mmol) was added. The solution was stirred for 15 min at 0° C. Asolution of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acidN-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxaidazol-5-yl)methoxy)-methyl)-2-phenylethyl)amide(456 mg, 0.97 mmol) in dichloromethane (3 mL) was added. The reactionmixture was stirred for 16 h, at room temperature. The reaction mixturewas diluted with ethyl acetate (150 mL). It was washed with saturatedsodium chloride solution (150 mL). The aqueous phase was extracted withethyl acetate (3×50 mL). The combined organic phases were washed withsaturated sodium hydrogen carbonate solution and dried over magnesiumsulfate. The solvent was removed in vacuo. The crude product waspurified by flash chromatogrphy on silica (60 g) with ethylacetate/heptane (2:1) to give 514 mg of(3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadizol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enylcarbamicacid tert-butylester.

[0726]¹H-NMR (CDCl₃) d 1.05-1.50 (m, 15H); 6.05 (m, 1H); 6.55 and 6.74(both m, together 1H); 7.05-7.85 (m, 12H).

[0727] (3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadizol-5-y)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)-carbamoyl)but-3-enylcarbamicacid tert-butylester (464 mg, 0.66 mmol) was dissolved indichloromethane (2 mL). The reaction mixture was cooled to 0° C.Trifluoroacetic acid (2 mL) was added. The reaction mixture was stirredfor 7 min at 0° C. The solvent was removed in vacuo. The residue wasdissolved in dichloromethane (50 mL), and the solvent was removed invacuo. This latter procedure was repeated two times. The crude productwas purified by flash chromatography on silica (30 g) withdichloromethane/methanol/25% aqueous ammonia (100:10:1). The product wasdissolved in ethyl acetate (3 mL) and 3 M hydrogen chloride in ethylacetate (0.7 mL) was added. The solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (50 mL) and the solvent wasremoved in vacuo to give 285 mg of the title compound as ahydrochloride.

[0728] HPLC: R_(f)=35.40 min (Method A1)

[0729]¹H-NMR (DMSO-d₆) d 1.03, 1.04, and 1.15 (all s, together 6H);2.35and 2.36 (both s, together 3H).

[0730] MS: 598.3 ([M+1]⁺).

[0731] C₃₅H₄₄N₅ClO₄.2H₂O calc. C62.72; H7.22; N10.45 found C62.72;H7.04; N10.30

Example 27

[0732] 2-Methyl-piperidine-4-carboxylic AcidN-{1-[N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2-naphthyl)ethyl}amide:

[0733] (R)N-Methyl-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamicAcid Tertbutyl Ester:

[0734] iso-Butylchloroformate (1.22 g, 9.0 mmol) was dropwise added to asolution of (R) N-methyl-N-tert-butoxycarbonyl-3-(2-naphthyl)alanine(3.0 g, 9 mmol) and N-methylmorpholine (0.91 g, 9.0 mmol) indichloromethane (40 mL) at -20° C. After 15 min at −20° C. acetamidoxim(1.33 g, 18 mmol) was added followed by addition of N-methyl-morpholine(0.91 g, 9 mmol). After 30 min at −20° C. the reaction mixture washeated to 20° C. and diluted with N,N-dimethylformamide (40 mL). Thedichloromethane was evaporated in vacuo and the reaction mixture washeated at 120° C. for 16 hours. The reaction mixture was poured intowater (120 mL) and extracted with ethyl acetate (180 mL). The organicphases were collected, washed with water (40 mL) and dried (magnesiumsulfate). The solution was concentrated in vacuo to give 3.5 g of crude(R)N-methyl-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphtyl)ethyl]carbamicacid tertbutyl ester that was used without further purification.

[0735] (R)N-Methyl-N-{1(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl}amineHydrochloride:

[0736] (R)N-Methyl-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphtyl)ethylcarbamicacid tertbutyl ester (3.3 g, 9.0 mmol) was dissolved in a saturatedsolution of hydrogen chloride in ethyl acetate (75 mL). After 3 hours at20° C. the reaction mixture was filtered to give 1.52 g of (R)N-methyl-N{1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl}aminehydrochloride.

[0737] m.p. 198-202° C.

[0738]¹H-NMR (DMSO-d₆) d 2.35(s, 3H); 2.68(s, 3H); 3.43(dd, 1H);3.80(dd, 1H); 5.29(dd, 1H); 7.30(d, 1H); 7.45-7.90(m, 7H).

[0739] HPLC: R_(t)=16.3 min (Method A1)

[0740] Calculated for C₁₆H₁₇N₃O₁HCl: C, 63.26; H, 5.97; N, 13.83%;found: C, 63,37; H, 6.11; N, 13.53%.

[0741]{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-carbamoyl)-2-(2-naphthyl)ethyl}carbamicAcid Tertbutyl Ester:

[0742] N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(1.12 g, 5.85 mmol) and 1-hydroxy-7-azabenzotriazole (0.8 g, 5.85 mmol)were added to a solution of (R)N-tert-butoxycarbonyl-3-(2-naphthyl)alanine (1.84 g, 5.85 mmol) inN,N-dimethylformamide (45 mL). After 30 min at 20° C. a mixture of (R)N-methyl-N-{1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl}aminehydrochloride (1.27 g, 4.18 mmol) and triethylamine (0.42 g, 4.18 mmol)in N,N-dimethylformamide (15 mL) were added. After 18 hours at 20° C.the reaction mixture was poured on water (200 mL) and extracted severaltimes with ethyl acetate (110 mL). The combined organic phases werewashed with aqueous citric acid (10%, 40 mL), a saturated solution ofsodium hydrogen carbonate (3×40 mL) and water (3×40 mL). After drying(magnesium sulfate) the solvent was concentrated in vacuo to give 2.4 gof crude {(1R)-1N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}2-(2-naphthyl)ethyl}carbamicacid tertbutyl ester which was used for the next step without furtherpurification.

[0743](2R)-2-Amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide(as a Trifluoroacetate):

[0744]{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-carbamoyl}2-(2-naphthyl)ethyl}carbamicacid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture oftrifluoroacetic acid (40 mL) and dichloromethane (40 mL) at 20° C. After10 min the reaction mixture was concentrated in vacuo and coevaporatedfrom dichloromethane (80 mL). The residue was crystallised from ethylacetate to give 1. 19 g of(2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide,trifluoroacetic acid.

[0745] mp 190-191° C.

[0746]¹H-NMR (DMSO-d₆) d 2.33(s, 3H); 2.88(s, 3H); 3.00-3.15(m, 2H);3.45(dd, 1H); 3.65(dd, 1H); 4.71 (t, 1H); 7.25-7.95(m, 14H).

[0747] HPLC: R_(t)=24.3 min (Method A1)

[0748] Calculated for C₂₉H₂₈N₄O₂, CF₃COOH: C, 64.35; H, 5.05; N, 9.68%;found: C, 64,30; H, 5.13; N, 9.44%. —2-Methylpiperidine-1,4-dicarboxylicAcid 1-tert-butyl Ester:

[0749] A suspension of 2-chloro-4-carboxy-6-methylpyridine (5.1 g, 3.0mmol) in hydrochloric acid (1N, 50 mL) was hydrogenated over palladiumon charcoal (20%, 0.95 g) at 150psi of hydrogen at 60° C. for 18 hours.The reaction mixture was filtered and concentrated in vacuo. The crudeproduct was dissolved in aqueous sodium hydroxide (1N, 53 mL) and asolution of di-tert-butyloxocarbonyl (6.35 g, 29.1 mmol) intetrahydrofuran (30 mL) was added. After 3 days at room temperature thereaction mixture was extracted with diethyl ether (50 mL) at pH 10. Theaqueous phase was adjusted to pH 2 with sulfuric acid (1N, 30 mL) andextracted with ethyl acetate (30 mL). The organic phase was washed withwater (4×15 mL), dried (magnesium sulfate) and concentrated in vacuo.The residue was chromatographed on silica (105 g) using ethyl acetateand heptane (1:1) as eluent to give 1.8 g of2-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester.

[0750] M.p. 109-112° C.

[0751]¹H-NMR (DMSO-d₆) d 1.13(d, 3H); 1.42(s, 9H); 1.70(m, 1H); 1.95(m,2H); 2.60(m, 1H); 3.12(m, 1H); 3.31(s, 1H); 3.77(m, 1H); 4.15(m, 1H);12.25 (s, 1H).

[0752] Calculated for C₁₂H₂₁N₁O₄: C, 59.24; H, 8.70; N, 5.76%; found: C,59.39; H, 9.13; N, 5.58%.

[0753]4-(1-{Methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamoyl)-2-methylpiperidine-1-carboxylicAcid Tert-Butyl Ester:

[0754] N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylicacid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8mL). After 30 min at 20° C. a solution of(2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide(as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine(0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18h at 20° C. the reaction mixture was poured on water (100 mL) andextracted several times with ethyl acetate (total 60 mL). The collectedorganic phases were washed with aqueous citric acid (10%, 20 mL), asaturated solution of sodium hydrogen carbonate (20 mL) and water (3×20mL). After drying (magnesium sulfate) the solution was concentrated invacuo to give 1.25g of crude4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylicacid tert-butyl ester that was used for the next step without furtherpurification.

[0755] HPLC: R_(t)=35.8min (Method A1)

[0756]4-(1-{Methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamoyl)-2-methylpiperidine-1-carboxylicacid tert-butyl ester (1.25 g, 1.81 mmol) was dissolved in a mixture oftrifluoroacetic acid (5 mL) and dichloromethane (5 mL). After 10 min at20° C. the reaction mixture was quenched with a saturated solution ofsodium hydrogen carbonate (45 mL) and extracted with dichloromethane (60mL). The organic phases were collected, dried (magnesium sulfate) andconcentrated in vacuo. The residue was chromatographed on silica gel(105 g) using a 10% mixture of ammonia in ethanol and dichloromethane(1:9) as eluent to give 0.90 g of the title compound, which was finallylyophilysed in 10% acetic acid.

[0757] HPLC: R_(t)=24.3min (Method A1)

[0758] PDMS: calculated: 589.7 [M] found: 589.5±1 [M+1]

Example 28

[0759] 4-Amino-cyclohexanecarboxylic AcidN-methyl-N-((1R)-1-[N-methyl-N{(R)-1-methylcarbamoyl-2-phenylethyl}carbamoyl]-2-(2-naphtyl)ethyl)amide:

[0760] 4-tert-Butoxycarbonylamino-cyclohexanecarboxylic Acid:

[0761] To a suspension of 4-aminocyclohexane carboxylic acid (3.0 g,20.95 mmol) in dioxan (40 mL) and water (20 mL) was added 20 ml of a 1 Msodium hydroxide solution. Di-tert-butyl dicarbonate (5.0 g, 23.05 mmol)was added and the mixture was stirred overnight. The mixture wasconcentrated in vacuo to 30 ml of solvent and 60 ml of ethyl acetate wasadded and the mixture was cooled to OOC. The mixture was acidified to pH2 with sodium bisulfate and the aqueous phase was extracted with ethylacetate (2×100 ml). The combined organic phases were washed with water(100 ml) and dried over magnesium sulfate and concentrated in vacuo togive 4.13 g of 4-tert-butoxycarbonylamino cyclohexanecarboxylic acid.1H-NMR (DMSO-d₆): dH 1.3 (s, 9H) 1.3-1.6 (m, 5H) 1.9 (m, 3H), 2.3 (m,1H) 6.7 (m, 1H)

[0762](4-[N-Methyl-N-{1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]-carbamoyl)-2-(2-naphtyl)ethyl}carbamoyl]cyclohexyl)carbamicAcid Tert-Butyl Ester:

[0763] To a suspension of 4-tert-butoxycarbonylaminocyclohexanecarboxylic acid (115 mg, 0.47) in 5 ml of dichloromethane wasadded 1-hydroxy-7-azabenzotriazole (64 mg, 0.47 mmol) in 0.5 mlN,N-dimethylformamide. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (100 mg, 0.52) was added and the solution was stirred for20 min. Diisopropylethylamine (120 mg, 0.94 mmol) andN-methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide(191 mg, 0.47 mmol) in 5 ml of dichloromethane was added and the mixturewas allowed to stand overnight at room temperature. The mixture waswashed with water (5 ml), sodium bicarbonate (5 ml) water (2×5 ml) andbrine (5 ml), dried over magnesium sulfate and concentrated in vacuo.The crude product was chromatographed on silica (20 g) with ethylacetate as eleuent to give 242 mg of(4-[N-Methyl-N{1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphtyl)ethyl}-carbamoyl]cyclohexyl)carbamicacid tert-butyl ester.

[0764]¹H-NMR (CDCl₃): d 1.0-1.8 (m, 8H) 1.5 (d, 9H) 2.4 (s, 3H) 2.7-3.3(m, 4H) 2.9 (s, 3H) 3.0 (s, 3H) 3.7 (m, 1H) 4.6 (m, 1H) 5.2-5.8 (m, 2H)7.0-7.8 (n), 12H)

[0765] 4-Amino-cyclohexanecarboxylic AcidN-methyl-N-((1R)-1-[N-methyl-N-{(1R)-1-methylcarbamoyl-2-phenylethyl}-carbamoyl]-2-(2-naphthyl)ethyl)amide:

[0766] To a solution of(4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethy]carbamoyl)-2-(2-naphthyl)-ethyl}carbamoyl]cyclohexyl)carbamicacid tert-butyl ester (240 mg, 0.38 mmol) in 1 ml dichloromethane wasadded 0.5 ml trifluoroacetic acid and the mixture was stirred for 5 min.Sodium bicarbonate was added until gas evolution has ceased, and themixture was extracted with dichloromethane (3×15 ml). The combinedorganic phases were washed with brine (5 ml), dried over magnesiumsulfate and concentrated in vacuo. The crude product was chromatographedon silica (16 g) with dichloromethane/methanol (4:1). The obtainedproduct was dissolved in 3 ml of methanol and added 40 ml of water and0.5 ml of acetic acid and lyophilized to give 99 mg of the titlecompound.

[0767]¹H-NMR (DMSO-d₆), (free base): d 1.2-1.5 (m, 8H) 2.05 (s, 3H) 2.65(d, 3H) 2.7 (s, 3H) 2.5-3.3 (m, 6H) 5.4 (m, 1H) 5.6 (m, 1H) 7.1-7.8 (m,12H)

[0768] HPLC: R_(t)=30.2 min (method A1)

Example 29

[0769]N-Methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-2-(N-methyl-N-{[(2-piperidinyl)methoxy]acetyl}amino)-3-(2-naphthyl)propinamide:

[0770] 2-(Carboxymethoxymethyl)piperidine-1-carboxylic AcidTert-Butylester:

[0771] To a solution ofN-(tert-butoxycarbonyl)-2-hydroxymethylpiperidine in 500 ml ofdichloroethane was added 180 mg of rhodium(II) acetate and the mixturewas heated to 80° C. Ethyldiazoacetate (3.7 ml, 35 mmol) in 180 mldichloroethane was added (during approx. 1 hour) and stirred at 80° C.for 6 hours. Another portion of ethyldiazoacetate (1.25 ml, 12 mmol) in40 ml of dichloroethane was added (over 20 min) and the mixture wasrefluxed at 80° C. for 7 h. The mixture was cooled to room temperatureand washed with sodium bicarbonate (150 ml) and brine (100 ml), driedover magnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (100 g) with pentane:ethyl acetate (4:1) aseluent to give 2.64 g of2-(((ethoxycarbonyl)methoxy)methyl)piperidine-1-carboxyl acidtert-butylester. The obtaining product was taken up in 40 ml of 1 M LiOHin water:methanol (1:3) and stirred at room temperature for 30 min. Themixture was concentrated in vacuo and water (20 mL) was added and thesolution was washed with ether (20 mL). The aqueous phase was acidifiedto pH 4 with 1 M aqueous hydrogen chloride and extracted with ethylacetate (50 ml), dried over magnesium sulfate and concentrated in vacuoto give 2.41 g of 2-(carboxymethoxymethyl)piperidine-1-carboxylic acidtert-butylester.

[0772] MHz-¹H-NMR (CDCl₃): d 1.45 (s, 9H) 1.55 (m, 2H) 1.85 (m, 2H) 3.1(m, 2H) 3.6 (m, 1H) 3.8 (m, 2H) 4.15 (s, 2H)

[0773]2-([N-Methyl-N-{1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]-carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylicAcid Tert-Butyl Ester:

[0774] To a solution of 2-(carboxymethoxymethyl)piperidine-1-carboxylicacid tert-butylester (225 mg, 0.82 mmol) in 5 ml of dichloromethane wasadded 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (173 mg,0.90 mmol) and the mixture was to stirred for 30 min.N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide(332 mg, 0.82 mmol) in dichloromethane (5mL) was added followed bydiisopropylethylamine (0.14 ml, 0.82 mmol) and the mixture was stirredovernight at room temperature. The mixture was washed with water (5 ml)aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), driedover magnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (20 g) with ethyl acetate to give 416 mg of2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylicacid tert-butyl ester.

[0775]¹H-NMR (CDCl₃) (selected peaks): d 1.45 (s, 9H) 2.45 (d, 3H) 2.75(d, 3H) 2.90 (d, 3H) 3.0 (s, 2H)

[0776] To a solution of2-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylicacid tert-butyl ester (388 mg, 0.60 mmol) in dichloromethane (1 mL) wasadded trifluoroacetic acid (1 mL) and the mixture was stirred for 10 minat room temperature. Then saturated sodium bicarbonate was added untilpH 8 and the organic phase was separated. The aqueous phase wasextracted with dichloromethane (2×10 ml) and the combined organic phaseswere washed with brine (5 ml), dried over magnesium sulfate andconcentrated in vacuo. The crude product was chromatographed on silica(15 g) with dichloromethane:methanol (9:1) to give 273 mg of the titlecompound.

[0777]¹H-NMR (CDCl₃) (selected peaks): d 5.3 (m, 1H) 5.75 (t, 1H)7.0-7.8 (m, 12H)

[0778] EI/SPMS: 559.5 (M+)

[0779] HPLC: R_(t)=32.0 (Method A1)

Example 30

[0780](2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(methyl[{piperidin-4-yloxy}acetyl]amino)-3-(2-naphthyl)propionamide:

[0781] 4-(Carboxymethoxy)piperidine-1-carboxylic Acid Tert-Butyl Ester:

[0782] To a solution of 4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester (5.0 g, 25 mmol) and rhodium(II) acetate (180 mg) in500 ml dichloroethane at 80° C. was added (over 90 min) ethyldiazoacetate (4.2 ml, 50 mmol) in 220 ml dichloroethane. The mixture wasstirred for 7 h and quenched with aqueous sodium bicarbonate (2×100 ml).The organic phase was isolated and washed with brine (2×100 ml), driedover magnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (80g) in petroleum ether:ethyl acetate (4:1)to give 3.4 g of 4-(ethoxycarbonylmethoxy)piperidine-1-carboxylic acidtert-butylester. The product was taken up in 40 ml of a 1 M lithiumhydroxide solution in water:methanol (1:3) and stirred for 60 min. Themixture was concentrated in vacuo and dissolved in 20 ml of water,acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted withethyl acetate (3×30 ml). The combined organic layers were washed withbrine (10 ml), dried over magnesium sulfate and concentrated in vacuo togive 1.79 g of 4-(carboxymethoxy)piperidine-1-carboxylic acid tert-butylester.

[0783]¹H-NMR (CDCl₃): d 1.45 (s, 9H) 1.55 (m, 2H) 1.9 (m, 2H) 3.1 (m,2H) 3.6 (m, 1H) 3.8 (m, 2H) 4.2 (s, 2H)

[0784] A solution of 4-(carboxymethoxy)piperidine-1-carboxylic acidtert-butyl ester (228 mg, 0.88 mmol), 1-hydroxy-7-azabenzotriazole (120mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (186 mg, 0.97 mmol) was stirred for 30 min at roomtemperature.N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(naphthalen-2-yl)propionamide(355 mg, 0.88 mmol) in 5 ml of dichloromethane was added followed bydiisopropylethylamine (0.2 ml, 1.14 mmol) and the mixture was stirredfor 2 days at room temperature. The mixture was washed with water (5 ml)aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), driedover magnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (30 g) with ethyl acetate as eluent to give391 mg of 4-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxy]piperidin-1-carboxylicacid tert-butylester. The product was taken up in 50%trifluoromethane/dichloromethane and allowed to stand for 10 min. Thensaturated sodium bicarbonate was added until pH was about 8 and theorganic layer was separated. The aqueous phase was extracted withdichloromethane (2×10 ml) and the combined organic phases were washedwith brine (5 ml), dried over magnesium sulfate and concentrated invacuo. The crude product was chromatographed on silica (15 g) withdichloromethane:methanol (9:1) to give 327 mg of the title compound.

[0785]¹H-NMR (CDCl₃) (selected peaks): d 3.75 (q, 2H) 5.5 (m, 1H) 5.8(t, 1H) 7.0-7.8 (m, 12H)

[0786] EI/SPMS: 544.5 (M+)

[0787] HPLC: R_(t)=28.9 (Method A1)

Example 31

[0788]2-[1-Methyl-2-(2-amino-(2-methylpropoxy))acetylamino]-N-(1-methyl-1-((1-methylcarbamoyl)-2-(2-phenylethyl)-3-(2-naphthyl))propionamide:

[0789] A solution of 2-butoxycarbonylamino-2-methylpropanol (5.0 g,26.46 mmol) and rhodium(II)acetate (90 mg) in dichloroethane (500 mL)was heated to 80° C. Ethyldiazoacetate (4.0 g, 34.78 mmol) was slowlyadded over a period of 1 hr., and the mixture was stirred at reflux for3 hr. Another 90 mg of rhodium(II)acetate was added and the mixture wasrefluxed for another 5 hr. The mixture was cooled overnight and 500 mlof saturated sodium bicarbonate was added, the yellow organic layer wasseparated and washed twice with saturated sodium bicarbonate (2×200 ml).The organic layer was dried over magnesium sulfate and concentrated invacuo. The yellow oil was taken up in 200 ml of 1 M Lithium hydroxide inmethanol:water (3:1) and stirred overnight. The solvent was removed invacuo to a minimum and water was added (pH>9) and the mixture was washedwith ether. Then 1 M hydrogen chloride was added until pH<4 and themixture was extracted with ethyl acetate, dried over magnesium sulfateand concentrated in vacuo to give 2.5 g (38%) of(2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid as a clear oil.

[0790] H¹-NMR (CDCl₃, 400 MHz) d 1.3 (s, 6H); 1.45 (s, 9H); 3.5 (s, 2H);4.15 (s, 2H); 9.9 (b, 1H).

[0791] A solution of (2-tert-butoxycarbonylamino-2-methylpropoxy) aceticacid (184 mg, 0.74 mmol), 1-hydroxy-7-azobenzotriazole (101 mg, 0.74mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide hydrocloric acid(157 mg, 0.82 mmol) in 9 ml of methylene chloride and 1 ml of DMF wasstirred for 15 min. TertN-methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(naphthalen-2-yl)propionamide(300 mg, 0.74 mmol) and diisopropylethylamine (96 mg, 0.74 mmol) in 1 mlof methylene chloride were added and allowed to stir overnight. Themixture was washed with saturated sodium bicarbonate, dried overmagnesium sulfate and concentrated in vacuo. The mixture waschromatographed on 100 ml of silica gel with ethyl acetate to give 360mg (76%) of 2-[1-methyl-2-(2-(t-butoxycarbonyl)amino-(2-methylpropoxy))acetylamino]-N-(1-methyl-1-((1-methylcarbamoyl)-2-(2-phenylethyl)-3-(2-naphthyl))propionamide.The obtained mixture was taken up in 1 ml of TFA and 1 ml of methylenechloride and stirred at 0° C. for 5 min. Then saturated sodiumbicarbonate was slowly added to the cooled solution and the organiclayer was separated, washed with sodium bicarbonate, dried overmagnesium sulfate and concentrated in vacuo to give 185 mg (47% from(2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid) of2-[1-methyl-2-(2-amino-(2-methylpropoxy))acetylamino]-N-(1-methyl-1-((1-methylcarbamoyl)-2-(2-phenylethyl)-3-(2-naphthyl))propionamideasan oil. The obtained oil was dissolved in dissolved in 0.1 N acetic acid(50 ml) and lyophilized to give an amorph white powder.

[0792] H¹-NMR (CDCl₃, 400 MHz, free amine) d 0.9 (d, 3H); 1.05 (d, 3H);2.35 (s, 3H); 2.75 (s, 3H); 2.8 (s, 3H); 2.9 (s, 2H); 3.0 (s, 2H);3.0-2.7 (m, 2H); 3.25 (m, 2H); 3.7 (t, 1H); 5.1 (dd, J=20 Hz, 1H); 5.8(t, 1H, amine); 7.8-6.9 (m, 12H).

[0793] HPLC: Rt=30.65 min in (A1); 97% purity

[0794] Calculated for C₃₁H₄₀N₄O₄, CH₃COOH, H₂O: C, 64.9%; H, 7.6%; N,9.1%; Found: C, 64.2%; H, 7.6%; N, 8.5%

Example 32

[0795](2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-Hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide;

[0796](2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-Butyldimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide;

[0797] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide(318 mg, 0.60 mmol) was dissolved in methanol (20 ml) and glacial aceticacid (0.48 ml, 8.4 mmol). 3 Å mol sieves (9 g) and a solution of(2R)-2-(tert-butyldimethylsilyloxy)propanal (1.33 g, 7.06 mmol) inmethanol (10 ml) were added successively. Sodium cyanoborohydride (220mg, 3.53 mmol) was added as a solid. The reaction mixture was stirred atroom temperature for 45 min, before a second batch of sodiumcyanoborohydride (220 mg, 3.53 mmol) was added. The reaction mixture wasstirred for 16 h at room temperature. The mol sieves was filtered offthrough a plug of celite. The celite was washed with methanol (200 ml).The solvents of the combined filtrates were removed in vacuo. Theresidue was dissolved in 1 N sodium hydroxide solution (50 ml) andtert-butyl methyl ether (50 ml). The phases were separated. The aqueousphase was extracted with tert-butyl methyl ether (3×50 ml). The combinedorganic layers were dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (35 g), using ethyl acetate/heptane/triethylamine (20:10:1) aseluent, to give 99 mg of(2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-butyldimethylsilyloxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide.

[0798]¹H-NMR (CDCl₃, selected values): d 0.04, 0.05, and 0.10 (all s,together 6H); 0.85 and 0.91 (both s, together 9H); 3.86 (m, 1H); 6.04and 6.08 (both d, together 1H); 6.89 (m, 1H).

[0799] MS: 701.2 [M+1].

[0800] HPLC: The RP-analysis was performed using UV detections at 214,254, 276, and 301 nm on a 218TP54 4.6 mm×250 mm 5 m C-18 silica column(The Seperations Group, Hesperia), which was eluted at 1 m Lumin at 42°C. The column was equilibrated with 5% acetonitrile in a bufferconsisting of 0.1% aqueous trifluoro acetic acid eluted by a gradient of0% to 90% of 0.1% trifluoro acetic acid in acetonitrile during 50 min:R_(t)=37.25 min.

[0801](2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-(tert-Butyldimethylsilyoxy)propylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-napthyl)prionyl)-N-methylamino-N-methyl-3-phenylpropionamide(99 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 ml).Tetra-n-butylammonium fluoride (0. 18 ml of a 1.1I M solution intetrahydrofuran, 0.2 mmol) was added. The solution was stirred for 3 h,before another portion of tetra-n-butylammonium fluoride (0.23 ml of a1.1 M solution in tetrahydorfuran, 0.25 mmol) was added. The reactionmixture was stirred for 2.5 h at room temperature and diluted with ethylacetate (50 ml). It was extracted with 10% sodium carbonate solution (30ml). The aqueous phase was extracted with ethyl acetate (20 ml). Theorganic layers were combined and dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified byflash-chromatography on silica (30 g), usingdichloromethanelmethanol/25% aqueous ammonia (100:10:1) as eluent, togive 28 mg of the title compound.

[0802]¹H-NMR (CDCl₃, selected values): d 3.65 and 3.72 (both m, together1H); 5.15 and 5.30 (both dd, together I H); 5.60 and 5.90 (both dd,together 1H); 6.03 and 6.05 (both d, together 1H); 6.78 (m, 1H).

[0803] MS: 587.2 [M+1].

[0804] HPLC: R_(t)=27.47 (A1).

[0805] R_(t)=27.12 (B1).

[0806] For biological testing it was transferred into the acetate byliophilization from 0.5 M acetic acid (20 ml).

Example 33

[0807](2E)-5-Amino-N-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-5-methyl-N-methylhex-2-enamide;

[0808] N-((1R)-1-Benzyl-2-(benzylamino)ethyl)-N-methylcarbamic AcidTert-Butylester;

[0809] A solution of oxalyl chloride (3.16 ml, 36.17 mmol) indichloromethane (50 ml) was coooled to −78° C. A solution ofdimethylsulfoxide (3.42 ml, 48.22 mmol) in dichloromethane (50 ml) wasadded dropwise. The reaction mixture was stirred for 5 min at −78° C. Asolution of N-((1R)-1-(hydroxymethyl)-2-phenylethyl)-N-methylcarbamicacid tert-butylester (6.40 g, 24.11 mmol) in dichloromethane (100 ml)was added dropwise over a period of 10 min. The solution was stirred for25 min at −78° C. Ethyldiisopropylamine (16.68 ml, 96.44 mmol) was addeddropwise at −78° C. The solution was warmed to −35° C., and immediatelycooled to −78° C. Glacial acetic acid (6.07 ml, 106.08 mmol) was added.The reaction mixture was warmed to room temperature and diluted withdichloromethane (150 ml). It was washed with saturated sodium chloridesolution (2×200 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was dissolved in methanol (200 ml).Benzylamine (2.6 ml, 24.1 mmol) was added. Glacial acetic acid (6.0 ml,106 mmol) and 3 Å mol sieves (32 g) were added. Sodium cyanoborohydride(1.00 g, 15.9 mmol) was added as a solid. The reaction mixture wasstirred for 1 h, before another portion of sodium cyanoborohydride (0.97g, 15.4 mmol) was added. The mixture was first stirred for 16 h at roomtemperature and successively left 3 days without stirring. The molsieves was filtered off through a plug of celite. The celite was washedwith methanol (200 ml). The solvent was removed in vacuo. The residuewas dissolved in 1 N sodium hydroxide solution/diethyl ether (250 ml/250ml). The phases were separated. The aqueous phase was extracted withdiethyl ether (2×100 ml). The combined organic layers were dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (230 g), usingdichloromethane/methanol/25% aqueous ammonia (first 100:10:1, then50:10:1) as eluent, to give 4.54 g ofN-((1R)-1-benzyl-2-(benzylamino)ethyl)-N-methylcarbamic acidtert-butylester.

[0810]¹H-NMR (CDCl₃): d 1.28 and 1.36 (both br, together 9H); 2.50-2.90(m, 8H); 3.70 (d, 1H); 3.88 (d, 1H); 4.45 and 4.65 (both br, together1H); 7.10-7.40 (m, 10H).

[0811] MS: 355.2 [M+H]⁺.

[0812] N-((1R)-1-Aminomethyl-2-phenylethyl)-N-methylcarbamic AcidTert-Butylester;

[0813] A suspension of 20% palladium hydroxide on charcoal (4.63 g) andN-((1R)-1-benzyl-2-(benzylamino)ethyl)-N-methylcarbamic acidtert-butylester (4.40 g, 12.4 mmol) was kept for 8 h under a hydrogenatmosphere at (pressure: 1 atm). The reaction mixture was flushed withnitrogen and filtered through a plug of celite. The solvent was removed.The crude product was purified by flash chromatography on silica (110g), using dichloromethanelmethanol/25% aqueous ammonia as eluent, togive 830 mg of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamicacid tert-butylester.

[0814]¹H-NMR (CDCl₃): d 1.29 and 1.36 (both s, together 9H); 1.40 (s,2H); 2.60-2.90 (m, 7H); 4.20 and 4.38 (both br, together 1H); 7.10-7.35(m, 5H).

[0815] N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamicAcid Tert-Butylester;

[0816] N-((1R)-1-Aminomethyl-2-phenylethyl)-N-methylcarbamic acidtert-butylester (830 mg, 3.14 mmol) was dissolved in dichloromethane (15ml). Triethylamine (0.44 ml, 3.14 mmol) was added. The solution wascooled to −78° C. A solution of methanesulfonyl chloride (0.24 ml, 3.14mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixturewas stirred for 16 h, while it was warming up to room temperature. Itwas diluted with dichloromethane (100 ml) and washed with saturatedsodium chloride solution (100 ml). It was dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (65 g), using ethyl acetatelheptane (2:1)as eluent, to give 990 mg ofN-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acidtert-butylester.

[0817]¹H-NMR (CDCl₃): d 1.30 and 1.40 (both br, together 9H); 2.60-3.00(m, 5H); 2.93 (br, 3H); 3.15-3.50 (m, 2H); 4.40 (br, 1H); 4.50 and 4.70(both br, together 1H); 7.05-7.35 (m, 5H).

[0818] N-((2R)-2-Methylamino-3-phenylpropyl)methansulfonamide;

[0819] At 0° C., trifluoroacetic acid (5 ml) was added to a solution ofN-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acidtert-butylester (913 mg, 2.67 mmol) in dichloromethane (5 ml). Thereaction mixture was stirred for 15 min at 0° C. The solvent was removedin vacuo without warming. The residue was dissolved in dichloromethane(50 ml) and the solvent was removed in vacuo. The latter procedure wasrepeated two times. The crude product was purified by flashchromatography on silica (20 g), using dichloromethane/methanol/25%aqueous ammonia as eluent, to give 658 mg ofN-((2R)-2-methylamino-3-phenylpropyl)methansulfonamide.

[0820]¹H-NMR (CDCl₃, selected values): d 2.39 (s, 3H); 2.70-3.00 (m,4H); 2.95 (s, 3H); 3.22 (dd, 1H), 7.15-7.35 (m, 5H).

[0821]N-((1R)-1-(N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicAcid Tert-Butylester;

[0822](2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (1.05 g, 3.2 mmol) was dissolved in N,N-dimethylformamide (2 ml)and dichloromethane (2 ml). Hydroxy-7-azabenzotriazole (434 mg, 3.2mmol) was added as a solid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (612 mg,3.2 mmol) was added. The solution was stirred for 5 min at 0° C. Asolution of N-((2R)-2-methylamino-3-phenylpropyl)methansulfonamide (703mg, 2.9 mmol) in dichloromethane (2 ml) was added. Ethyldiisopropylamine(0.50 ml, 2.90 mmol) was added. The solution was stirred for 27 h, whileit was warming up to room temperature. It was diluted with ethyl acetate(200 ml) and extracted with 1N hydrochloric acid (100 ml). The aqueousphase was extracted with ethyl acetate (50 ml). The combined organiclayers were washed with saturated sodium hydrogen carbonate solution anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (45 g),using ethyl acetate/heptane (2:1) as eluent, to give 1.037 g ofN-((1R)-1-(N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester.

[0823]¹H-NMR (CDCl₃, selected values): d 1.30 and 1.34 (both br,together 9H); 7.00-7.90 (m, 12H).N-((2R)-2-(N-Methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide;

[0824] At 0° C., trifluoroacetic acid (4 ml) was added to a solution ofN-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester (997 mg, 1.8 mmol) in dichloromethane (4 ml). Thesolution was stirred for 15 min at 0° C. The solvent was removed invacuo at 20 ° C. The residue was dissolved in dichloromethane and thesolvent was removed in vacuo. The latter procedure was repeated twotimes. The crude product was purified by flash chromatography on silica(45 g), using dichloromethanelmethanol/25% aqueous ammonia as eluent, togive 646 mg ofN-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide.

[0825]¹H-NMR (CDCl₃, selected values): d 1.87, 2,33, 2.38, 2,50, 2.62,2.80, 2.82, 2.88, and 2,92 (all s, together 9H); 3.62 and 3.76 (both dd,together 1H); 4.56 and 4.72 (both br, together 1H); 4.84 and 5.02 (bothbr, together 1H); 6.90-7.95 (m, 12H).

[0826] MS: 454.2 [M+H]⁺.

[0827](3E)-4-(N-((1R)-1-(N-((1R)-1-Benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicAcid Tert-Butyl Ester;

[0828] (2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (352 mg,1.45 mmol) was dissolved in N,N-dimethylformamide (2 ml) anddichloromethane (2 ml). Hydroxy-7-azabenzotriazole (197 mg, 1.45 mmol)was added as a solid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (278 mg,1.45 mmol) was added. The solution was stirred for 15 min at 0° C. Asolution ofN-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide(598 mg, 1.32 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine(0.23 ml, 1.32 mmol) were added successively. The solution was stirredfor 18 h, while it was warming up to room temperature. It was dilutedwith ethyl acetate (100 ml) and extracted with 1 is N hydrochloric acid.The aqueous phase was extracted with ethyl acetate (50 ml). The combinedorganic layers were washed with saturated sodium hydrogen carbonatesolution (100 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (60 g), using ethyl acetate/heptane (2:1) as eluent to give740 mg of (3E)A-4-(N-((1R)-1-(N-((1R)-1benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester.

[0829]¹H-NMR (CDCl₃, selected values): d 2.60, 2.80, 2.89, 2.92, 3.06,and 3.17 (all s, 259 together 9H); 6.06 and 6.25 (both d, together 1H);6.82 and 6.96 (both m, together 1H); 7.00-7.85 (m, 12H).

[0830](3E)-4-(N-((1R)-1-(N-((1R)-1-Benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butyl ester (729 mg, 1.07 mmol) was dissolved indichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroaceticacid (3 ml) was added. The reaction mixture was stirred for 15 min at 0°C. The solvents were removed in vacuo at 20° C. The residue wasdissolved in dichloromethane (100 ml) and the solvent was removed invacuo. The latter procedure was repeated two times. The crude productwas purified by flash chromatography on silica (60 g), usingdichloromethanelmethanol/25% aqueous ammonia as eluent, to give 440 mgof the title compound as free base.

[0831]¹H-NMR (CDCl₃,selected values): d 1.10, 1.11, 1.1.14, and 1.15(all s, together 6H); 2.64, 2.71, 2.88, 2.90, 3.06, 3.18 (all s,together 9H); 4.76 and 5.00 (both br, together 1H); 4.95 and 5.09 (bothdd, together 1H); 6.08 and 6.28 (both d, together 1H); 6.83 and 7.00(both m, together 1H).

[0832] MS: 579.0 [M+H]⁺.

[0833] HPLC: R_(t)=31.98 min (A1).

[0834] R_(t)=27.53 min (B1).

[0835] For biological testing the title compound was transferred intoits acetate by liophilization from 40 ml 0.5 M aqueous acetic acid.

Example 34

[0836] 3-(1-Aminoethyl)benzoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide:

[0837] 3-(1-(N-tertbutoxycarbonyl)aminoethyl) benzoic Acid:

[0838] Ammonium acetate (10.6 g, 138 mmol) was evaporated from dryethanol (100 mL), and redissolved in dry methanol (100 mL) overmolecular sieves (3A, 3 g). 3Acetylbenzonitrile (2.0 g, 13.8 mmol) wasadded. After 30 minutes at room temperature sodium cyanoborohydride(0.87 g, 138 mmol) was added and the reaction mixture was stirred for 18hours. The reaction mixture was concentrated in vacuo and redissolved inwater (100 mL). Concentrated hydrochloric acid was added until pH 2, andthe aqueous solution was extracted with ethyl acetate (2×1 00 mL). Theaqueous phase was adjusted to pH 11 with solid potassium hydroxide, andextracted with dichloromethane (2×100 mL). The combined organic phaseswere dried (magnesium sulfate) and concentrated in vacuo. A concentratedsolution of hydrogen chloride in ethyl acetate added (100 mL) was, andthe solution was concentrated in vacuo. The residue was dissolved inethanol (25 mL) and sulphuric acid (9N, 25 mL) was added. After 16 hoursat room temperature and 2 hours at reflux temperature the ethanol wasremoved by evaporation in vacuo and the residual aqueous mixture wasadjusted to pH >8 using solid potassium hydroxide.Ditertbutyldicarbonate (2.0 g) dissolved in tetrahydrofuran (100 mL) wasadded at 0° C. After 18 hours at room temperature the reaction mixturewas concentrated in vacuo and redissolved in water (100 mL). Solidcitric acid was added until pH 5. The reaction mixture was extractedwith dichloromethane (2×100 mL), and the combined organic phases wasdried (magnesium sulfate) and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (3×40 cm) using ethanoland dichloromethane (1:9) as eluent to give 1.1 g of3-(1-(N-tertbutoxycarbonyl)aminoethyl)benzoic acid.

[0839] 3-(1-(N-tert-Butyloxycarbonyl)aminoethyl)benzoic acid (132 mg,0.50 mmol), 1-hydroxy-7-azabenzotriazole (68 mg, 0.50 mmol) and1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50mmol) were dissolved in N,N-dimethylformamide(3 mL) and stirred for 15min.(2R)-N-Methyl-N-((1R)-2-phenyl)-1-(methylcarbamoyl)ethyl)-2-methylamino-3-(2-naphtyl)propionamide(100 mg, 0.25 mmol) dissolved in dichloromethane (6 mL) was addedfollowed by addition of diisopropylethylamine (0.085 mL, 0.50 mmol) andthe mixture was stirred for 20 hours. The reaction mixture wasevaporated in a stream of nitrogen and the residue was dissolved inethyl acetate (25 mL). The mixture was washed with aqueous sodiumhydrogen carbonate (2×25 mL, 5%) and aqueous potassium hydrogen sulfate(25 mL, 5%). The organic phase was dried (sodium sulfate) and evaporatedin vacuo. The residue was dissolved in dichloromethane (2.5 mL), cooledto 0-4° C. and treated with trifluoroacetic acid (2.5 mL) for 10 minutesat 0-4° C. The volatiles were removed with a stream of nitrogen an theoily residue was dissolved in 0.1% triflouroacetic acid in acetonitrileand water (7:3, 10 mL) and diluted with water (290 mL). This solutionwas submitted to semipreperative HPLC purification using a 25×200 mm C18column and using a linear gradient of 25-40% acetonitrile in watercontaining 0.1M ammonium sulfate (pH 2.5). The product was purified inthree runs and after ion exchange on a Waters Seppak C18 the effluentwas lyophilised to give the title compound.

[0840] PD-MS: Calculated 551.7 (M+1); Found 551.3 (M+1)

[0841] HPLC: Rt=31.8 min (Method A1)

[0842] Rt=33.93 min (Method B1)

Example 35

[0843] 5-Amino-5-methyl-hex-2-enoic acid((1R)-1-(((1R)-1-((2R)-2-hydroxypropylcarbamoyl)-2-phenylethyl)methylcarbamoyl)-2-t2-naphthyl)ethyl)methylamide:

[0844] The title compound was prepared analogously to example 1.

[0845]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 1.09 (d, 3H);1.19 (s, 6H); 2.97 (s, 3H); 2.99 (s, 3H); 5.15 (dd, 1H); 5.53 (dd, 1H);6.12 (d, 1H)

[0846] HPLC: r_(t)=31.8 min. (A1)

[0847] PDMS: m/z 573.7 (M+H)⁺

Example 36

[0848] (4-(1-Aminocyclobutyl)but-2-enoic acid((1R)-1-(((1R)-1-(1-methylcarbamoyl-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide:

[0849] The title compound was prepared analogously to example 1.(4-(1-Aminocyclobutyl)but-2-enoic acid was prepared as in R. Graf, Org.Synth. 46, 51 (1966) and example 1.

[0850]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 2.26 (s, 3H);2.98 (s, 3H); 3.00 (s, 3H); 5.15 (dd, 1H); 5.57 (dd, 1H); 6.11 (d, 1H).

[0851] HPLC: r_(t)=32.2 min. (A1)

Example 37

[0852] 5-Amino-5-methyl-hex-2-enoic acid((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(2-thienyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide.

[0853] This compound was prepared analogously to example 1.

[0854]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 1.10 (d, 3H);1.14 (s, 3H; 1.15 (s, 3H); 2.18 (d, 2H); 2.95 (s, 3H); 3.05 (s, 3H);5.28 (dd, 1H); 5.72 (dd, 1H); 6.07 (d, 1H).

[0855] HPLC: r_(t)=30.4 min. (A1)

Example 38

[0856](2R)-2-(N-[(2R)-2-(N-[(2-Aminobutoxy)acetyl]-N-methylamino)-3-(2-naphthyl)propionyl]-N-methylamino)-N-methyl-3-phenylpropionamide:

[0857] (2-(tert-Butoxycarbonylamino)butoxy)acetic Acid:

[0858] To a solution of (1-(hydroxymethyl)propyl)carbamic acidtert-butylester (7.2 g, 39 mmol) in 1 ,2-dichloroethane (500 ml)rhodium(II)acetate (180 mg) was added and the mixture was heated to 80°C. Ethyldiazoacetate (6.0 ml, 57 mmol) in 1,2-dichloroethane (1 80 ml)was added over a period of 60 min and the mixture was heated at 80° C.for 6 hours. Then another portion of ethyldiazoacetate (2.0 ml, 19 mmol)in 1 ,2-dichloroethane (40 ml) was added and the mixture was refluxedfor 7 hours. The mixture was cooled to room temperature and washed withsodium bicarbonate (2×1 00 ml) and brine (100 ml), dried over magnesiumsulfate and concentrated in vacuo. The crude product was chromatographedon silica (300 g) is with pentane/ethyl acetate 7:3 as eluent to give4.3 g of (2-(tert-butoxycarbonylamino)butoxy)acetic acid ethylester. Theproduct was dissolved in of 1 M lithium hydroxide in water/methanol 1:3(40 ml) and stirred at room temperature for 4 hours. The mixture wasconcentrated in vacuo and water (100 mL) was added and the solution waswashed with ether (20 mL). The aqueous phase was acidified to pH 4 with1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml),dried over magnesium sulfate and concentrated in vacuo to give 2.46 g of(2-(tert butoxycarbonylamino)butoxy)acetic acid.

[0859]¹H-NMR (CDCl₃): d 0.95 (t, 3H) 1.45 (s, 9H) 1.60 (m, 3H) 3.55 (m,2H) 4.10 (s, 2H)

[0860] To a solution of (2-(tert-butoxycarbonylamino)butoxy)acetic acid(1.1 g, 4.5 mmol) in dichloromethane (20 ml) were added1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.5 mg,A5.0 mmol) and the mixture was stirred for 30 min.(2R)-N-methyl-2-methylamino-N-((1R)-1-methyl-carbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide(605 mg, 1.5 mmol) in dichloromethane (10 ml) was added followed bydiisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirredfor 2 hours at room temperature. The mixture was washed with water (10ml), saturated aqueous sodium bicarbonate (10 ml), water (2×10 ml),brine (10 ml), dried over magnesium sulfate and concentrated in vacuo.The crude product was chromatographed on silica (40 g) with ethylacetate/heptane 4:1 to give 766 mg of(1-[{N-methyl-N-((1R)-1-[N-methyl-N-{(1R)-1-(methylcarbamoyl)-2-phenylethyl}carbamoyl]-2-(2-naphthyl)ethyl)carbamoyl}methoxymethyl]-propyl)carbamicacid tert-butylester. The obtained product was taken up in 50%trifluoroacetic acid in dichloromethane (5 ml) and stirred for 10 min.Then saturated sodium bicarbonate was added until pH 8 and the phaseswere separated. The aqueous phase was extracted with dichloromethane(2×10 ml) and the combined organic phases were washed with brine (5 ml),dried over magnesium sulfate and concentrated in vacuo to give(2R)-2-(N-[(2R)-2-(N-[{2-aminobutoxy}acetyl]-N-methylamino)-3-(2-naphthyl)propionyl]-N-methylamino)-N-methyl-3-phenylpropionamideas an oil. The product was redissolved in water (30 ml) and acetic acid(2 ml) was added and the mixture was lyophilized to give 645 mg of theacetate salt of the title compound as an amorphous powder.

[0861] LC-MS: 533.0 (M+H)⁺

[0862] HPLC: R_(t)=31.1 (Method A1)

[0863]¹H-NMR (DMSO) (selected peaks): d 0.6-0.8 (m, 3H) 2.65 (d, 3H)2.75 (s, 3H) 5.35 (dd, 1H) 5.65 (dd, 1H) 7.1-7.9 (arom, 12H)

Example 39

[0864](2R)-N-Methyl-2-(N-methyl-N-((2R)-2-(N-methyl-N-((((2S)-pyrrolidin-2-yl)methoxy)acetyl)amino)-3-(2-naphthyl)propionyl)amino)-3-phenylpropionamide

[0865] (2S)-2-(((Carboxy)methoxy)methyl)pyrrolidin-1-carboxylic AcidTert-Butylester

[0866] To a solution of N-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) wasadded and the mixture was heated to 80° C. Ethyldiazoacetate (3.9 ml, 37mmol) in 1,2-dichloroethane (180 ml) was added over a period of 90 minand the mixture was heated at 80° C. for 3 hours. Then another portionof ethyldiazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) wasadded and the mixture was refluxed for 6 hours. The mixture was cooledto room temperature and washed with saturated sodium bicarbonate (2×100ml) and brine (100 ml), dried over magnesium sulfate and concentrated invacuo. The crude product was chromatographed on silica (300 g) withpetrol ether/ethyl acetate 4:1 as eluent to give 4.7 g of(2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acidtert-butylester. The obtained product was taken up in 50 ml of 1 Mlithium hydroxide in water/methanol 1:3 and stirred at room temperatureovernight. The mixture was concentrated in vacuo, water (20 mL) wasadded and washed with ether (20 mL). The aqueous phase was acidified topH 4 with I M aqueous hydrogen chloride and extracted with ethyl acetate(200 ml), dried over magnesium sulfate and concentrated in vacuo to give3.6 g of (2S)-2-(((carboxy)methoxy)methyl)pyrrolidin-1-carboxylic acidtert-butylester.

[0867]¹H-NMR (CDCl₃): d 1.45 (2, 9H) 1.90 (m, 4H) 3.55 (t, 2H) 3.60 (m,3H) 4.10 (s, 2H) 10.6 (s, 1H)

[0868] To a solution of(2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acidtert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg,4.95 mmol) and the mixture was stirred for 30 min.(2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide(605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed bydiisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirredfor 2 hours at room temperature. The mixture was washed with water (10ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml),dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was chromatographed on silica (40 g) with ethyl acetate/heptane4:1 to give 760 mg of(2S)-2-([N-methyl-N(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylicacid tert-butylester. The obtained product was taken up in 50%trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10min. Then saturated sodium bicarbonate was added until pH 8 and thephases were separated. The aqueous phase was extracted withdichloromethane (2×10 ml) and the combined organic phases were washedwith brine (5 ml), dried over magnesium sulfate and concentrated invacuo. The product was redissolved in water (30 ml) and acetic acid (2ml) was added and the mixture was liophilized to give 720 mg of theacetate salt of the title compound as an amorphous powder.

[0869]¹H-NMR (DMSO) (selected peaks): d 0.75 (m, 1H) 1.35 (m, 1H) 1.6(m, 1H) 1.7 (m, 1H) 2.65 (d, 3H) 2.75 (d, 3H) 3.95 (d, 2H) 5.35 (dd, 1H)5.55 (dd, 1H)

[0870] LC-MS: 544.8 (M+H)⁺

[0871] HPLC: R_(t)=31.1 (Method A1)

Example 40

[0872]3-((2R)-2-(N-((2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylAcetate

[0873] To a solution of (2-t-butoxycarbonylamino-2-methylpropoxy) aceticacid (504 mg, 2.0 mmol) in dichloromethane (10 ml) were added1-hydroxy-7-azabenzotriazole (278 mg, 2.0 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429 mg, 2.3mmol) and the mixture was stirred for 30 min.3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-propylacetate (500 mg, 1.0 mmol) in dichloromethane (10 mL) was added followedby diisopropylethylamine (0.23 ml, 1.32 mmol) and the mixture wasstirred overnight at room temperature. The mixture was washed with water(10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10ml), dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was chromatographed on silica (60 g) with ethyl acetate/heptane4:1 to give 623 mg of3-((2R)-2-(N-((2R)-2-(N-((2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthy)propionyl)-N-methylamino)-3-phenylpropionylamino)-propylacetate as an oil. The obtained product was taken up in 50%trifluoroacetic acid in dichloromethane (3 ml) and stirred for 10 min.Then saturated sodium bicarbonate was added until pH 8 and the organicphase was separated. The aqueous phase was extracted withdichloromethane (2×10 ml) and the combined organic phases were washedwith brine (5 ml), dried over magnesium sulfate and concentrated invacuo. The product was redissolved in water (30 ml) and the mixture wasliophilized to give 434 mg of the title compound as an amorphous powder.

[0874]¹H-NMR (CDCl₃) (selected peaks): d 1.1 (s, 3H) 1.2 (s, 3H) 2.0 (s,3H) 2.15 (s, 3H) 5.7 (m, 2H) 5.25 (m, 1H)

[0875] LC-MS : 619.6 (M+H)⁺

[0876] HPLC: R_(t)=33.2 (Method A1)

Example 41

[0877] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide:

[0878] (2R)-N, N-Dimethyl-2-methylamino-3-phenylpropionamide

[0879] To a solution of(2R)-2-(tert-butoxycarbonylmethylamino)-3-phenylpropionic acid (10.0 g,36.0 mmol) in dichloromethane (200 ml) was added1-hydroxy-7-azabenzotriazole (6.8 g, 50.0 mmol) and I-ethyl-3-(3-3.0dimethylaminopropyl)carbodiimide hydrochloride (1 0.0 g, 55.0 mmol) andthe mixture was stirred for 30 min. Then dimethylamine hydrochloride(4.1 g, 50.0 mmol) in dichloromethane (100 ml) and diisopropylethylamine(19.0 ml, 110 mmol) were added and the mixture was stirred overnight atroom temperature. The mixture was washed with water (100 ml) aqueoussodium bicarbonate (100 ml), water (2×100 ml), brine (100 ml), driedover magnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (400 g) with dichloromethane/methanol 20:1 togive 6.3 g of(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3phenylpropionic acidN,N-dimethylamide. The product was dissolved in 50% trifluoroacetic acidin dichloromethane (5 ml) and stirred for 10 min. Then saturated sodiumbicarbonate was added until pH 8 and the phases were separated. Theaqueous phase was extracted with dichloromethane (2×10 ml) and thecombined organic phases were washed with brine (5 ml), dried overmagnesium sulfate and concentrated in vacuo to give 4.58 mg of(2R)-N,N-dimethyl-2-methylamino-3-phenylpropionamide.

[0880]¹H-NMR (CDCl₃): d 2.3 (s, 3H) 2.7 (s, 3H) 2.9 (s, 3H) 2.8-3.4 (m,2H) 4.45 (m, 1H) 7.1-7.3 (m, 5H)

[0881]N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicAcid Tert-Butylester

[0882] To a solution of(2R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid(8.78 g, 26.6 mmol) in dichloromethane (30 ml) were added1-hydroxy-7-azabenzotriazole (3.62 g, 26.6 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.54 mg,28.9 mmol) and the mixture was stirred for 30 min. Then(2R)-N,N-dimethyl-2-methylamino-3-phenylpropionamide (4.58 g, 22.2 mmol)in dichloromethane (15 ml) and diisopropylethylamine (4.94 ml, 28.9mmol) were added and the mixture was stirred overnight at roomtemperature. The mixture was washed with water (20 ml), aqueous sodiumbicarbonate (20 ml), water (2×20 ml), brine (20 ml), dried overmagnesium sulfate and concentrated in vacuo. The crude product waschromatographed on silica (400 g) with ethyl acetatelheptane 1:4 to give6.64 g ofN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester.

[0883]¹H-NMR (CDCl₃) (selected peaks for rotamers): d 1.1 and 1.4 (twos, 9H) 2.2, 2.3, 2.7 and 2.8 (four s, 6H) 2.35 and 2.6 (two s, 3H) 2.9and 3.0 (two s, 3H)

[0884] A solution ofN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester (6.6 g, 12.8 mmol) in 50% trifluoroaceticacid/dichloromethane (15 ml) was stirred for 10 min. Then saturatedsodium bicarbonate was added until pH 8 and the organic phase wasseparated. The aqueous phase was extracted with dichloromethane (2×20ml) and the combined organic phases were washed with brine (10 ml),dried over magnesium sulfate and concentrated in vacuo to give 4.2 g of(2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.

[0885]¹H-NMR (CDCl₃): d 2.7 (s, 3H) 2.75 (s, 3H) 2.85 (s, 3H) 2.9-3.15(m, 4H) 3.7 (t, 1H) 5.8 (t, 1H) 7.1-7.8 (arom, 12H)

[0886] To a solution of(2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.59, 2.1mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml)and stirred for 60 min and concentrated in vacuo. Then a 10% aqueoussolution of sodium carbonate (30 ml) and dioxane (30 ml) were addedfollowed by 9H-fluorenylmethyl-succinimidyl carbonate (0.67 g, 2.1 mmol)and stirred overnight. The mixture was washed with petrol ether (2×20ml) and the aqueous layer was acidified with 4N sulphoric acid (pH˜3)and extracted with ethyl acetate (3×50 ml). The combined organic layerswere washed with 1N sulfuric acid, water (4×20 ml), brine (20 ml), dried(Magnesiumsulfate) and concentrated in vacuo. The obtained product wasprecipitated from dichloromethane/ether and filtered to give 280 mg of(2E)-5-(((9H-flouren-9-yl)methoxy)carbonylamino)-5-methyl-hex-2-enoicacid, which was used without further purification.

[0887] To a solution of(2E)-5-(((9H-flouren-9-yl)methoxy)-carbonylamino)-5-methylhex-2-enoicacid (280 mg, 0.77 mmol) in dichloromethane (5 ml) were added1-hydroxy-7-azabenzotriazole (126 mg, 0.92 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (207 mg,1.08 mmol) and the mixture was stirred for 30 min. Then2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(386 mg, 0.92 mmol) in dichloromethane (5 ml) and diisopropylethylamine(0.17 ml, 1.00 mmol) were added and the mixture was stirred overnight atroom temperature. The mixture was washed with water (20 ml), saturatedaqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml),dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was chromatographed on silica (400 g) with ethyl acetate/heptan1:1 to give 401 mg of((3E)-4-(N-((1R)-1-(N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid 9H-flouren-9-ylmethyl ester. The obtained product was dissolved in20% piperidine in dimethylformamide (10 ml) and stirred for 30 min. Themixture was chromatographed on silica (20 g) withdichloromethane/methanol/ammonia 89:10:1 to give 228 mg of(2E)-5-amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamideas an oil. The product was redissolved in water (30 ml) and acetic acid(2 ml) was added and the mixture was lyophilized to give 645 mg of theacetate salt of the title compound as an amorphous powder.

[0888] LC-MS: 543.0 (M+H)⁺

[0889] HPLC: R_(t)=32.9 (Method A1)

[0890]¹H-NMR (DMSO) (selected peaks): d 1.0 (s, 6H) 1.8 (s, 6H) 2.4 (s,3H) 2,7 (s, 3H) 2.8 (s, 3H)

Example 42

[0891] 5-Amino-5-methyl-hex-2-enoic Acid(1-{[2-(2-fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}2-(2-naphthyl)ethyl)methylamide.

[0892]{4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}-2-(2naphthyl)ethyl)methylcarbamoyl]-1,1dimethyl-but-3-enyl}carbamicAcid Tert-Butyl Ester.

[0893] (2E)-5-(tert-Butyloxycarbonylamino)-5methylhex-2-enoic acid (0.19g; 0.783 mmol was dissolved in methylene chloride (10 ml).1Hydroxy-7azbenzotriazole (0.12 g; 0.861 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.17 g;0.900 mmol) was added and the reaction mixture was stirred 15 min atroom temperature.N-[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(0.33 g; 0.783 mmol) and diisopropyl ethylamine (0.15 ml; 0.861 mmol)was added and the reaction mixture was stirred 12 hours at roomtemperature.

[0894] Methylene chloride (50 ml) was added and the reaction mixture waswashed with water (50 ml), sodium hydrogen sulfate (10%; 50 ml), sodiumhydrogen carbonate (sat; 50 ml), water (50 ml) and dried (magnesiumsulfate). The solvent was removed in vacuo to afford 0.366 g of{4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamic acid tert-butylester.

[0895]{4-[(1-{[2-(2-Fluorophenyl)-1-methylcarbamoylethyl]methylcarbamoyl}2-(2-naphthyl)ethyl)methylcarbamoyl]-1,1-dimethyl-but-3-enyl}carbamicacid tert-butyl ester (0.36 g; 0.557 mmol) was dissolved in methylenechloride (3 ml). Trifluoro acetic acid (3 ml) was added and the reactionmixture was stirred 5 min at room temperature. Methylene chloride (25ml), sodium hydrogen carbonate/sodium carbonate (3 ml) and sodiumhydrogen carbonate (s) was added until pH=8. The organic phase was dried(magnesium sulfate) and the solvent was removed in vacuo. The residuewas lyophylised to afford 0.237 g of the title compound.

Example 43

[0896] (2Z)-5-Amino-3,5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[0897] (Z)(1,1,3-Trimethyl-4-(methyl-(1-(methyl-(1-methylcarbamoyl-2-phenyl ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester (0.009 g; 0.014mmol.) was dissolved in methylene chloride (0.12 mL) and trifluoroacetic acid (0.08 mL) was added. The reaction mixture was stirred 5 minat room temperature. Water (0.100 mL) was added. The solvent was removedin vacuo to afford 0.007 g (2Z)-5-Amino-3,5-dimethylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide; trifluoro acetic acid salt.

[0898] ESMS: M_(w)=542.4

[0899] HPLC: R_(t)=34.82

Example 44

[0900] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)amide:

[0901] 4-Formyl-3,5-dimethoxyphenol:

[0902] To a solution of 3,5-dimethoxyphenol (50 g, 320 mmol) inphosphorous oxychloride (60 mL, 650 mmol) at 0° C. was addeddimethylformamide (37 mL, 490 mmol) over a period of 30 min and themixture was warmed to room temperature and stirred overnight. Themixture was added to icewater (600 mL) and the mixture was washed withether (3×200 mL). Then an 32% aqueous solution of sodium hydroxide wasadded until pH was 5.5 and the compound precipitated. The precipitatewas separated and washed with water (100 mL) and ether (100 mL) anddried in vacuo. The precipitate was recrystallized from ethanol (600 mL)to give 22.6 g of 4-formyl-3,5-dimethoxyphenol.

[0903] bp. 224-226° C.

[0904]¹H-NMR (DMSO): d 3.75 (s, 6H) 6.1 (s, 2H) 10.1 (s, 1H)

[0905] Ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate:

[0906] To a suspension of 4-formyl-3,5-dimethoxyphenol (22.6 g, 124mmol) and potassium tert-butoxide (15.3 g, 136 mmol) indimethylformamide (125 mL) was added ethyl 5-bromovalerate (28.5 g, 136mmol) in dimethylformamide (125 mL) over a period of 20 min. The mixturewas heated at 11 0° C. for 6 h and concentrated in vacuo. To theobtained product was added ethyl acetate (400 mL) and the mixture wasfiltered. The filtrate was washed with water (100 mL), 1 N sodiumhydroxide (2×50 mL), and brine (3×100 mL), dried (magnesium sulfate),and concentrated in vacuo to 37 g of ethyl5-(4-formyl-3,5-dimethoxyphenoxy)valerate.

[0907]¹H-NMR (CDCl₃): d 1.25 (t, 3H) 1.85 (m, 4H) 2.4 (m, 2H) 3.9 (s,6H) 4.05 (t, 2H) 4.15 (q, 2H) 6.1 (s, 2H) 10.3 (1H)

[0908] 5-(4-Formyl-3,5-dimethoxyphenoxy)valeric Acid:

[0909] To a solution of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy) valerate(37 g, 119 mmol) in methanol (200 mL) was added 4 N sodium hydroxide(200 mL) and the mixture was stirred for 2 h. The methanol was removedin vacuo, water (100 mL) was added and the mixture was washed with ethylacetate (100 mL) and dichloromethane (2×100 mL). The aqueous layer wasacidified with 12 N hydrochloric acid until pH-3 and extracted withethyl acetate (2×200 mL). The combined organic layers were washed withbrine (2×50 mL), dried (magnesium sulfate) and concentrated in vacuo.The obtained product was recrystallized from ethanol to give 26 g of5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid.

[0910] bp. 134-136° C.

[0911]¹H-NMR (CDCl₃): d 1.85 (m, 4H), 2.45 (m, 2H) 3.85 (s, 6H) 4.05 (m,2H) 6.05 (s, 2H) 10.3 (s, 1H)

[0912] N-Methyl-PAL-Resin for Solid-Phase Synthesis (PAL Defined as inF. Albericio et al., J. Org. Chem., 55 (1990) pp. 3730-3743):

[0913] Aminomethylated polystyrene resin (10 g, 7.8 mmol, purchased fromBachem AG, # D-1005) and 1-hydroxybenzotriazole hydrate(1 g, 6.6 mmol)in dimethylformamide (100 mL) were shaken overnight. The resin wasfiltered and the resin was repeatedly swelled in dichloromethane anddimethylformamide until a homogeneous resin was obtained. The resin waswashed with 5% diisopropylethylamine in dimethylformamide (2×100 mL) anddimethylformamide (100 mL), successively. A solution of5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid (6.6 g, 23 mmol),1-hydroxybenzotriazole hydrate (3.5 g, 23 mmol) anddiisopropylcarbodiimide (3.6 mL, 23 mmol) indimethylformamide/dichloromethane 2:1 (50 mL) was added. After 5 h atroom temperature the resin was filtered and washed withdimethylformamide (3×100 mL), dichloromethane (3×50 mL) anddichloromethane/methanol 1:1 (3×100 mL) and dried with a stream ofnitrogen. To the resin in dimethylformamide (50 mL) were added 5% aceticacid in dimethylformamide (50 mL) and 40% methylamine in methanol (3.0mL, 39 mmol) and the mixture was shaken for 20 min. Sodiumtriacetoxyborohydride (8.3 g, 39 mmol) was added and the mixture wasshaken overnight. The mixture was filtered and the resin was washed withdimethylformamide (3×50 mL), dichloromethane (3×50 mL),dichloromethane/methanol 1:1 (3×50 mL), ether (3×50 mL) and dried with astream of nitrogen to give 10 g of N-Methyl-PAL-Resin (loading:0.35-0.45 mmol/g based on N-analysis).

[0914] Calc: N 1.82% Found: N 1.47%

[0915] The N-Methyl-PAL-Resin (450 mg) was washed with 5%diisopropylethylamine in dichloromethane (2×2 mL), dichloromethane (3×2mL) and dimethylformamide (3×2 mL) and then swelled in dimethylformamide(7 mL). Then(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid (163 mg, 0.36 mmol) in dimethylformamide (1 mL),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (137 mg, 0.36 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) in dimethylformamide (1ml) and diisopropylethylamine (123 mL, 0.72 mmol) in dimethylformamide(1 mL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). Then 20% piperidine indimethylformamide (5 mL) was added and the mixture was shaken for 20min, filtered and washed with dimethylformamide (3×2 mL),dichloromethane (3×2 mL) and dimethylformamide (2 mL). Then(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (163 mg, 0.36 mmol) in dimethylformamide (1 mL),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (137 mg, 0.36 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (49 mg, 0.365 mmol) in dimethylformamide (1mL) and diisopropylethylamine (123 ml, 0.72 mmol) in dimethylformamide(1 mL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). Then 20% piperidine indimethylformamide (5 mL) was added and the mixture was shaken for 20min, filtered and washed with dimethylformamide (3×2 mL),dichloromethane (3×2 mL) and dimethylformamide (2 mL). Then(2E)-5-(N-tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (88 mg,0.36 mmol) in dimethylformamide (1 mL),0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate is (137 mg, 0.36 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) in dimethylformamide (1mL) and diisopropylethylamine (123 mL, 0.72 mmol) in dimethylformamide(1 mL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). The resin was cooled to 0° C. and50% trifluoroacetic acid in dichloromethane (4 mL) was added and themixture was shaken for 10 min at 0° C. The resin was filtered and washedwith 50% trifluoroacetic acid in dichloromethane (2×0.5 mL) and thecombined filtrates were concentrated under a stream of nitrogen. Theobtained product was dissolved in acetonitrile/water 1:20 (10 mL) andapplied to a C-18 Sep-Pak Classic® cartridge (0.25 g, purchased fromWaters™), which had been prewashed with acetonitrile (10 mL) and water(10 mL). Then water/trifluoroacetic acid 99.9:0.1 (5 mL), followed bywater/acetonitrile/trifluoroacetic acid 89.9:10:0.1 (4 mL) was runthrough the Sep-Pak® and the filtrate was discarded. Then the Sep-Pakwas washed with water/acetonitrile/trifluoroacetic acid 64.9:35:0.1 (4mL) and the filtrate was diluted with water (11 mL) and lyophilized to52 mg of the title product.

[0916] HPLC: (A1) R_(t)=35.03 min (B1) R_(t)=36.93 min

[0917] LC-MS: 579.0 (m+1)⁺

Example 45

[0918] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0919] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[0920] Yield: 44 mg

[0921] HPLC: (A1) R_(t)=30.22 min (B1) R_(t)=32.10 min

[0922] LC-MS: 559.2 (m+1)⁺

Example 46

[0923] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0924] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[0925] Yield: 38 mg

[0926] HPLC: (A1) R_(t)=30.68 min (B1) R_(t)=32.33 min

[0927] LC-MS: 529.0 (m+1)⁺

Example 47

[0928] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(1-naphthyl)ethyl)amide:

[0929] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionic acid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methyloxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid instead of(2R)-2-(N-((9H-fluoren-9yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid. Yield: 70 mg

[0930] HPLC: (A1) R_(t)=34.52 min (B1) R_(t)=36.38 min

[0931] LC-MS: 579.0 (m+1)⁺

Example 48

[0932] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0933] The title compound was prepared analogously to example 44(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0934] Yield: 49 mg

[0935] HPLC: (A1) R_(t)=30.52 min (B1) R_(t)=32.03 min

[0936] LC-MS: 529.0 (m+1)⁺

Example 49

[0937] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(1-naphthyl)ethyl)amide:

[0938] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(I-naphthyl)propionic acid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0939] Yield: 51 mg

[0940] HPLC: (A1) R_(t)=30.20 min (B1) R_(t)=31.70 min

[0941] LC-MS: 559.2 (m+1)⁺

Example 50

[0942] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0943] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0944] Yield: 26 mg

[0945] HPLC: (A1) R_(t)=25.75 min (B1) R_(t)=26.98 min

[0946] LC-MS: 539.2 (m+1)+

Example 51

[0947] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2,3,4,5,6-pentafluorophenyl)ethyl)amide:

[0948] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2,3,4,5,6-pentafluorophenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0949] Yield: 42 mg

[0950] HPLC: (A1) R_(t)=31.05 min (B1) R_(t)=32.00 min

[0951] LC-MS: 599.0 (m+1)⁺

Example 52

[0952] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide:

[0953] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0954] Yield: 31 mg

[0955] HPLC: (A1) R_(t)=25.68 min (B1) R_(t)=27.00 min

[0956] LC-MS: 509.2 (m+1)+

Example 53

[0957] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-(1-naphthyl)ethyl)amide:

[0958] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2,3,4,5,6-pentafluorophenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0959] Yield: 38 mg

[0960] HPLC: (A1) R_(t)=34.88 min (B1) R_(t)=36.78 min

[0961] LC-MS: 619.0 (m+1)⁺

Example 54

[0962] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0963] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2,3,4,5,6-pentafluorophenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0964] Yield: 25 mg

[0965] HPLC:(A1) R_(t)=30.72 min (B1) R_(t)=32.32 min

[0966] LC-MS: 599.0 (m+1)¹

Example 55

[0967] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-(2,3,4,5,6-pentafluorophenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-phenylethyl)amide:

[0968] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2,3,4,5,6-pentafluorophenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0969] Yield: 30 mg

[0970] HPLC: (A1) R_(t)=30.88 min (B1) R_(t)=32.55 min

[0971] LC-MS: 569.0 (m+1)⁺

Example 56

[0972] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(4-methoxyphenyl)ethyl)amide:

[0973] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0974] Yield: 25 mg

[0975] HPLC: (A1) R_(t)=25.95 min (B1) R_(t)=27.23 min

[0976] LC-MS: 509.4 (m+1)⁺

Example 57

[0977] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(2,3,4,5,6-pentafluorophenyl)ethyl)amide:

[0978] The title compound was prepared analogously to example 44 with(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2,3,4,5,6-pentafluorophenyl)propionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid and(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(1-naphthyl)propionicacid.

[0979] Yield: 35 mg

[0980] HPLC: (A1) R_(t)=31.20 min (B1) R_(t)=32.47 min

[0981] LC-MS: 569.0 (m+1)¹

Example 58

[0982](2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-3-(2-naphthyl)propionamide

[0983] N-((1R)-1-Carbamoyl-2-phenylethyl)-N-methylcarbamic AcidTert.-Butylester.

[0984] A solution of(2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionic acid(4.00 g, 14.32 mmol) in N,N-dimethylformamide (1 0 ml) was cooled to 0°C. Ammonium hydrogen carbonate (5.66 g, 71.60 mmol) was added as asolid. 1-Hydroxybenzotriazole hydrate (1.94 g, 14.32 mmol) andsuccessively N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (2.75 g, 14.32 mmol) were added. The suspension wasstirred for 16 h, while warming up to room temperature. The reactionmixture was diluted with ethyl acetate (150 ml) and extracted withsaturated sodium chloride solution/water (200 ml/300 ml). The aqueousphase was extracted with ethyl acetate (3×100 ml). The combined organiclayers were washed with saturated sodium hydrogen carbonate solution anddried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash-chromatography on silica (70 g),using ethyl acetate/heptane as eluent, to give 2.80 g ofN-((1R)-1-carbamoyl-2-phenylethyl)-N-methylcarbamic acidtert.-butylester.

[0985]¹H-NMR (CDCl₃): d 1.29 and 1.40 (both s, together 9H); 2.74 (s,3H); 2.95 (m, 1H); 3.37 (m, 1H); 4.75 and 4.96 (both m, together 1H);5.55, 5.73, 5.95, and 6.17 (all br, together 2H); 7.05-7.40 (m, 5H).

[0986] N-((1R)-1-Aminomethyl-2-phenylethyl)-N-methylcarbamic AcidTert-Butylester.

[0987] N-((1R)-1-Carbamoyl-2-phenylethyl)-N-methylcarbamic acidtert.-butylester (2.73 g, 9.81 mmol) was dissolved in tetrahydrofuran(10 ml). The solution was cooled to 5° C. A suspension of sodiumborohydride (816 mg, 21.58 mmol) in tetrahydrofuran (10 ml) was added. Asolution of iodine (1.24 g, 4.91 mmol) was added dropwise. After theaddition was completed, the solution was heated to reflux for 16 h. Itwas cooled to 5° C. A 10% solution of ammonium chloride in water (60 ml)was added 15 dropwise. The solution was warmed to 50° C. for 1 h. It wascooled to room temperature. 1N sodium hydroxide solution was added untilpH 14. It was extracted with tert-butyl methyl ether (4×100 ml). Thecombined organic layers were dried over magnesium sulfate. The solventwas removed in vacuo. The crude product was purified by flashchromatography on silica (150 g) using dichloromethane/methanol/25%aqueous ammonia 100:1:0:1 as eluent to give 453 mg ofN-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acidtert-butylester.

[0988]¹H-NMR (CDCl₃): d 1.29 and 1.36 (both s, together 9H); 2.60-2.90(m, 7H); 4.20 and 4. 38 (both br, together 1H); 7.10-7.35 (m, 5H).

[0989]N-((1R)-1-Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamic AcidTert-Butylester.

[0990] At 0° C., cyclopropylisothiocyanate (0.32 ml) was added to asolution of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acidtert-butylester (410 mg, 1.6 mmol) in dichloromethane (4 ml). Thereaction mixture was first stirred at 0° C. for 10 min, and successivelyfor 2.5 h at room temperature. The solvent were removed in vacuo. Thecrude product was purified by flash chromatography on silica (50 g)using ethyl acetate/heptane as eluent to give 492 mg of N-((1R)1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamic acidtert-butylester.

[0991]¹H-NMR (CDCl₃): d 0.62 (br, 2H); 1.26 and 1.36 (both s, together9H); 2.37 (br, 1H); 2.60-3.00 (m, 5H); 3.60 (m, 1H); 3.98 (m, 1H); 4.60(m, 1H); 6.30 and 6.85 (both m, together 2H); 7.10-7.35 (m, 5H).

[0992] N-Cyclopropyl-N′-((2R)-2-methylamino)-3-phenylpropyl)thiourea.

[0993]N-((1R)-1-Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamic acidtert-butylester (404 mg, 1.1 mmol) was dissolved in dichloromethane (2ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) wasadded. The reaction mixture was stirred for 7 min. The solvents wereremoved in vacuo. The residue was dissolved in dichloromethane and thesolvent was removed in vacuo. This latter procedure was repeated twotimes. The crude product was purified by flash chromatography on silica(9 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) aseluent, to give 255 mg ofN-cyclopropyl-N′-((2R)-2-methylamino)-3-phenylpropyl)thiourea.

[0994]¹H-NMR (CDCl₃): d 0.64 (br, 2H); 0.85 (m, 2H); 2.38 (s, 3H); 2.45(m, 1H); 2.77 (ABX, 2H); 2.99 (m, 1H); 3.58 (m, 1H); 3.74 (m, 1H); 6.25(m, 1H); 7.15 (m, 1H); 7.15-7.35(m, 5H).

[0995]N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicAcid Tert-Butylester.

[0996](2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (290 mg, 0.88 mmol) was dissolved in dichloromethane (2 ml) andN,N-dimethylformamide (2 ml). 1-Hydroxy-7-azabenzotriazole (120 mg, 0.88mmol) was added as a solid. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (202 mg,1.06 mmol) was added. The solution was stirred for 20 min.N-Cyclopropyl-N′-((2R)-2-methylamino)-3-phenylpropyl)thiourea (231 mg,0.88 mmol) was dissolved in dichloromethane (2 ml) and added. Thereaction mixture was stirred for 16 h. It was diluted with ethyl acetate(100 ml) and extracted with 1 N hydrochloric acid (100 ml). The aqueousphase was extracted with ethyl acetate (2×10 ml). The combined organiclayers were washed with saturated sodium hydrogen carbonate solution(100 ml) and dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(45 g) using ethyl acetate/heptane 1:1 as eluent to give 350 mg ofN-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenyl-ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamicacid tert-butylester.

[0997]¹H-NMR (CDCl₃): d 0.06, 0.19, 0.30, 0.40, 0.55 (all m, together4H); 1.25 and 1.33 (both s, together 9H); 1.41 and 1.60 (both m,together 1H); 2.12 and 1.27 (both s, together 3H); 2.70-3.00 (m, 6H);3.25 (m, 1H); 3.55 (m, 1H); 4.00 and 4.15 (both m, together 1H); 5.02and 5.37 (both t, together 1H); 5.12 and 5.25 (both m, together 1H);5.90 and 5.99 (both br, together 1H); 6.60 (m, 1H); 7.10-7.85 (m, 12H).

[0998](2R)-N-((1R)-1-Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.

[0999]N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acidtert-butylester (579 mg, 1.01 mmol) was dissolved in dichloromethane (2ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) wasadded. The solution was stirred for 5 min. The solvents were removed invacuo without warming. The residue was dissolved in dichloromethane (100ml) and the solvent was removed in vacuo. This latter procedure wasrepeated two times. The crude product was purified by flashchromatography on silica (45 g) using dichloromethanelmethanol/25%aqueous ammonia 100:10:1 as eluent to give 201 mg of(2R)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-napthyl)propionamide.

[1000]¹H-NMR (CDCl₃): d 0.63 (m, 2H); 0.85 (m, 2H); 1.90 (s, 3H); 2.38(br, 1H); 2.65 (s, 3H); 2.70-3.05 (m, 5H); 3.60 (m, 1H); 4.05 (m, 1H);5.23 (m, 1H), 6.30 (m, 1H); 6,90-7.85 (m, 13H).

[1001](3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicAcid Tert-Butylester

[1002] (2E)-5-tertButoxycarbonylamino-5-methylhex-2-enoic acid (1 82 mg,0.75 mmol) 9 was dissolved in N,N-dimethylformamide (2 ml) anddichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (102 mg, 0.75 mmol)was added. The solution was cooled to 0° C.N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (144 mg,0.75 mmol) was added. The solution was stirred for 15 min at 0° C.(2R)-N-((1R)-1Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(178 mg, 0.37 mmol) was dissolved in dichloromethane and added to thereaction mixture. Ethyldiisopropylamine (0.13 ml, 0.75 mmol) was added.The solution was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (200 ml) and washed with10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueoussolution 1.5 was extracted with ethyl acetate (3×50 ml). The combinedorganic layers were washed with saturated sodium hydrogen carbonatesolution (150 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (45 g) to give 89 mg of (3E)-4-(N-((1R)-1-(N-((1R)-1benzyl-2-(3-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acidtert-butylester.

[1003]¹H-NMR (CDCl₃, selected values): d-0.08, 0.11, 0.20, 0.30, and0.60 (all m, together 4H); 3.34 (dd, 1H); 4.00 (m, 1H); 5.52 and 5.87(dd, 1H); 6.00 and 6.05 (both d, together 1H); 6.65 and 6.80 (both m,together I H).

[1004](3E)-4-(N-((1R)-1-(N-((1R)-1-Benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamicacid tert-butylester (63 mg, 0.09 mmol) was dissolved in dichloromethane(2 ml). The solution was cooled to 0° C. Trifluoracetic acid (2 ml) asadded. The solution was stirred for 15 min at 0° C. The solvent wasremoved in vacuo at 20° C. The residue was dissolved in dichloromethane(50 ml), and the solvent was removed in vacuo. This latter procedure wasrepeated two times. The residue was dissolved in ethyl acetate (2 ml).Heptane (5 ml) was added. The precipitation was filtered off and wascharacterized to be 50 mg of the title compound as trifluoroacetic acidsalt.

[1005]¹H-NMR (DMSO-d₆, selected values): d 0.25-0.75 (m, 4H); 3.15 (dd,1H); 6.41 (m, 1H).

[1006] HPLC:

[1007] The RP-HPLC analysis was performed using UV detection at 254nmand a Lichrosorp RP-18 5 mM column, which was eluted at 1 ml/minute. Twosolvent systems were used:

[1008] Solvent system I: 0.1% Trifluoro acetic acid in acetonitrile.Solvent system II: 0.1% Trifluoroacetic acid in water.

[1009] The column was equilibrated with a mixture composed of 20% ofsolvent system I and 80% of solvent system II. After injection of thesample a gradient of 20% to 80% of solvent system I in solvent system IIwas run over 30 minutes. The gradient was then extended to 100% ofsolvent system I over 5 minutes followed by isocratic elution with 100%of this system for 6 minutes.

[1010] R_(t) 20.42 min.

[1011] MS: found 599.6 [M+H]⁺, calc: 599.3.

[1012] m.p.: 138-145° C.

[1013] C₃₅H₄₅N₅O₂S.CF₃COOH.2H₂O calc.: C_(59.26;) H 6.72; N 9.34 found:C_(59.23;) H 6.64; N 8.83.

Example 59

[1014](2R)-2-(N-[{2-Amino-2-methylpropoxy}acetyl]-N-methylamino)-N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)propionamide:

[1015] (2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid:

[1016] A solution of 2-tert-butoxycarbonylamino-2-methylpropanol (5.0 g,26 mmol) and rhodium(II)acetate (90 mg) in 1,2-dichloroethane (500 ml)was heated to 80° C. Then ethyl diazoacetate (4.0 g, 35 mmol) was addedover a period of 1 h, and the mixture was stirred at reflux for 3 h.Another portion of rhodium(II)acetate (90 mg) was added and the mixturewas refluxed for another 5 h. The mixture was cooled overnight andsaturated sodium bicarbonate (500 ml) was added, the phases wereseparated and the organic layer was washed with saturated sodiumbicarbonate (2×200 ml), dried (magnesium sulfate) and concentrated invacuo. The obtained product was dissolved in 1 M lithium hydroxide inmethanol/water 3:1 (200 ml) and stirred overnight. The solvent wasremoved in vacuo, water was added (pH>9) and the Mixture was washed withether (200 ml). Then 1 M hydrochloric acid was added until pH<4 and themixture was extracted with ethyl acetate (200 ml), dried (magnesiumsulfate) and concentrated in vacuo to give 2.5 g of(2-tert-butoxycarbonylamino-2-methylpropoxy)acetic acid.

[1017]¹H-NMR (CDCl₃): d 1.3 (s, 6H) 1.45 (s, 9H) 3.5 (s, 2H) 4.15 (s,2H) 9.9 (b, 1H).

[1018] To a solution of2-tert-butoxycarbonylamino-2-methylpropoxy)acetic acid (480 mg, 1.9mmol) in dichloromethane (10 ml) were added 1-hydroxy-7-azabenzotriazole(264 mg, 1.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (409 mg, 2.1 mmol) and the mixture was stirred for 30 min.Then(2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide(434 mg, 0.97 mmol) in dichloromethane (5 ml) and diisopropylethylamine(0.22 ml, 1.3 mmol) were added and the mixture was stirred overnight atroom temperature. The mixture was washed with water (20 ml), saturatedaqueous sodium bicarbonate (20 ml), water (2×20 ml), brine (20 ml),dried over magnesium sulfate and concentrated in vacuo. The crudeproduct was chromatographed on silica (400 g) with ethyl acetate/pentane7:3 to give 432 mg of(2-[{N-((1R)-1-[N-{(1R)-1-(dimethylcarbamoyl)-2-phenylethyl}-N-methylcarbamoyl]-2-(2-naphthyl)ethyl)-N-methylcarbamoyl}methoxy]-1,1-dimethylethyl)carbamicacid tert-butylester. The obtained product was dissolved in 50%trifluoroacetic acid in dichloromethane (3 ml) and stirred for 10 min.Then saturated sodium bicarbonate was added until pH 8 and the phaseswere separated. The aqueous phase was extracted with dichloromethane(2×10 ml) and the combined organic phases were washed with brine (5 ml),dried (magnesium sulfate) and concentrated in vacuo. The product wasredissolved in water (30 ml) and the mixture was lyophilized to give 300mg of the title compound.

[1019]¹H-NMR (CDCl₃) (selected peaks): d 1.2 (d, 6H) 2.2 (s, 6H) 2.7 (s,3H) 2.8 (s, 3H) 4.0 (q, 2H) 5.7 (m, 1H) 5.8 (m, 1H) 7.1-7.8 (m, 12H).

[1020] HPLC (A1): R_(t)=32.8 (B1): R_(t)=34.6

[1021] LC-MS: 547.0 (M+H)⁺

Example 60

[1022] 5-methylamino-hex-2-enoic Acid ((1R)-1-(((1R)-2-(3,4-difluorophenyl)-1-methylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide

[1023] This compound was prepared analogously to example 1.2-(3,4-difluorophenyl)-alanine was substituted for phenylalanine.

[1024]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 1.22 (s, 6H);2.10 (d, 3H); 2.71 (s, 3H); 2.85 (s, 3H); 5.22 (dd, 1H); 5.86 (dd, 1H);6.17 (d, 1H).

[1025] HPLC :r_(t)=33.18min. (A1)

[1026] PDMS: m/z 566.0 (M+H)⁺

Example 61

[1027] 5-methylamino-hex-2-enoic Acid((1R)-1-(((1R)-2-phenyl-1-ethylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide

[1028] This compound was prepared analogously to example 1.

[1029]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 0.61 (t, 3H);1.05 (s, 6H); 1.98 (s, 3H); 2.24 (s, 3H); 2.97 (d, 3H); 5.57 (dd, 1H);5.85 (dd, 1H); 6.07 (d, 1H).

[1030] HPLC: r_(t)=33.0 min (A1)

[1031] PDMS : m/z 544.0 (M+H)⁺

Example 62

[1032] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-me-thyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide

[1033](2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(thiophen-2-yl)propionicAcid

[1034] (2R)-2-(tert-Butoxycarbonylamino)-3(thiophen-2-yl)propionic acid(5.00 g; 18.4 mmol) was dissolved in tetrahydrofuran (60 ml).Methyliodide (9.2 ml; 147 mmol) was added and the solution was cooled toOOC. Sodiumhydride (60% in oil; 1.90 g; 55.3 mmol) was added in portionsand the reaction mixture was stirred at room temperature for two days.Ethyl acetate (50 ml) and water (20 ml) were added dropwise. The solventwas removed in vacuo and the residue was dissolved in ether (30 ml) andwater (30 ml). The phases were separated and the organic phase waswashed with saturated aqueous sodium hydrogencarbonate (3ml). Theaqueous phase were mixed. Citric acid (5% (aq)) was added to pH 3 andthe aqueous phase was extracted with ethyl acetate (4×30 ml). Thecombined organic phases were washed with water (2×30 ml), aqueous sodiumthiosulfate (5%; 30 ml), water (30 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The residue was dissolved in ether (10ml) and dicyclohexylamine (8.5 ml) was added and the mixture was left ina refrigerator overnight. The precipitate was filtered and washed withether (2×15 ml) and then redissolved in methylene chloride and washedwith a mixture of water (15 ml) and sodium hydrogensulfate (15 ml;10%(aq)). The aqueous phase was washed with methylene chloride (3×15ml). The combined organic phases were dried over magnesium sulfate andthe solvent was removed in vacuo to give 5.10 g of(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(thiophen-2-yl)propionicacid.

[1035]¹H-NMR: (CDCl₃) (major rotamer) d 1.38 (s, 9H); 2.85 (s, 3H); 3.14(dd, 1H); 3.56 (dd, 1H); 4.62 (dd, 1H); 6.80-7.11 (3 arom. H).

[1036]N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamicAcid Tert-Butylester

[1037](2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(thiophen-2-yl)propionicacid (2.00 g; 7.01 mmol ) was dissolved in methylene chloride (10 ml).1-Hydroxybenzotriazole (0.95 g; 7.01 mmol) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.48 g ;7.71 mmol) were added. The solution was stirred for 15 min. atroomtemperature. Methylamine (40% in methanol; 0.38 ml; 7.71 mmol) anddiisopropylamine (1.2 ml; 7.01 mmol) were added and the reaction mixturewas stirred at room temperature for two days. Water (10 ml) andmethylene chloride (10 ml) were added to the solution. The phases wereseparated and the organic phase was washed with aqueous sodiumhydrogensulfate (10%; 15 ml), saturated aqueous sodium hydrogencarbonate(15 ml), dried over magnesium sulfate and the solvent was removed invacuo. The crude product was chromatographed on silica (4×40 cm) withethyl acetate/methylene chloride (1:1) as eluent to give 1.18 g ofN-Methyl-N-(1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamic acidtert-butylester.

[1038]¹H-NMR: (CDCl₃) (major rotamer) d 1.42 (s, 9H); 2.80 (s, 6H); 3.20(m, 1H); 3.49 (dd, 1H); 4.92 (dd, 1H); 6.81-7.18 (arom.; 3H).

[1039] (2R)-N-Methyl-2-methylamino-3-(thiophen-2-yl)propionamide

[1040]N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamicacid tert-butylester (1.17 g; 3.92 mmol) was dissolved in methylenechloride (4 ml). The reaction was cooled to 0° C. and triflouroaceticacid was added. The mixture was stirred at room temperature for 1.5hour. Water (30 ml) and solid sodium hydrogencarbonate were added to pH8. The phases were separated. The aqueous phase was extracted withmethylene chloride (4×20 ml). The combined organic phases were driedover magnesium sulfate and the solvent was removed over vacuo to afford0.70 g of (2R)-N-methyl-2-methylamino-3-(thiophen-2-yl)propionamide.

[1041]¹H-NMR: (CDCl₃)d 2.35 (s; 3H); 2.85 (d; 3H); 3.08 (dd; I H); 3.25(dd; 1H); 3.39 (dd; 1H); 6.88-7.29(arom.; 3H)

[1042]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic Acid Tert Butylester.

[1043] 2-(tert Butoxycarbonylmethylamino)-3-(2-naphthyl) propionic acid(1.20 g ;3.55 mmol) was dissolved in methylene chloride (10 ml).1-Hydroxy-7-azabenzotriazol (0.48 g ; 3.55 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.75 g ;3.90 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.

[1044] (2R)N-Methyl-2methylamino-3-(thiophen-2-yl)propionamide (0.70 g;3.55 mmol) was dissolved in methylene chloride (10 ml) and added.Diisopropylamine (0.61 ml ; 3.55 mmol) was added. The reaction mixturewas stirred at room temperature for 2 days. Methylene chloride (10 ml)and water (10 ml) were added to the reaction mixture. The phases wereseparated and the organic phase was washed with aqueous sodiumhydrogensulfate (10%; 20 ml), saturated aqueous sodium hydrogencarbonate(20 ml). The organic phase was dried over magnesium sulfate and thesolvent was removed in vacuo. The crude product was chromatographed onsilica (2×20 cm) using ethylacetate/heptane (1:1) as eluent to afford1.38 g of N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1(methylcarbamoyl)-2-(thiophen-2-yl)ethyl )carbamoyl)-2-(2-naphthyl)ethyl) carbamic acid tert butylester.

[1045]¹H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1.33 (s, 9H);2.27 (d, 3H); 2.81 (s, 3H); 2.95 (s, 3H); 5.02 (dd; 1H); 5.22 (dd, 1H).

[1046](2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide

[1047]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-l(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl) carbamic acid tert butylester (1.38 g ;2.71 mmol) was dissolved in methylene chloride (6 ml) andtriflouroacetic acid (4 ml) was added. The reaction mixture was stirredfor 1 hour at room temperature. Water (30 ml) and solid sodiumhydrogencarbonate were added to pH 8. The is phases were separated andthe aqueous phase was extracted with methylene chloride (4×20 ml). Theorganic phase was dried over magnesium sulfate and the solvent wasremoved over vacuo to afford 1.06 g of(2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl )-3-(2-naphthyl)propionamide.

[1048]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.95 (s, 3H);2.28 (d, 3H); 2.55 (s, 3H); 3.90 (dd, 1H); 5.42 (dd, 1H).

[1049]((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicAcid tert butylester.

[1050] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(0.30 g; 1.22 mmol) was dissolved in methylene chloride (10 ml).1-Hydroxy-7-azabenzotiazole (0.17 g; 1.22 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g;1.34 mmol) were added. The reaction mixture was stirred for 15 min atroom temperature.

[1051](2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.22 mmol) in methylene chloride(10 ml) was added to the reaction mixture. Diisopropylamine (0.21 ml;1.22 mmol) was added. The reaction mixture was stirred 12 hours at roomtemperature. Water (10 ml) and methylene chloride (10 ml) were added.The phases were separated and the organic phase was washed with aqueoussodium hydrogensulfate (10%; 20 ml), saturated aqueous sodiumhydrogencarbonate (20 ml), dried over magnesium sulfate and the solventwas removed in vacuo. The crude product was chromatographed on silica(2×20 cm) using ethyl acetate/methylene chloride (1:1) as eluent toafford 0.66 g of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert butylester.

[1052] ((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert butylester (0.66g; 1.04 mmol) was dissolved in methylenechloride (3 ml) and triflouroacetic acid (2 ml) was added. The reactionmixture was stirred 5 min at room temperature. Water (2 ml) and solidsodium hydrogencarbonate was added to pH 8. The phases were seperatedand the aqueous phase was extracted with methylene chloride (4×15 ml).The organic phase was dried over magnesium sulfate and the solvent wasremoved in vacuo to afford 0.53 g of the title compound.

[1053]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d 2.31 (d, 3H);2.63 (s, 3H); 2.91 (s, 3H); 5.18 (dd, 1H); 5.55 (dd, 1H); 6.19 (d, 1H).

[1054] HPLC: r_(t)=30.3 min (A1).

[1055] PDMS: m/z 534.8 (M+H)⁺

Example 63

[1056] (2E)-5-Methyl-5-methylaminohex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide

[1057] (2E)-5-(N-(tertButoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic Acid.

[1058] (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid(5.00 g; 20.6 mmol) was dissolved in tetrahydrofuran (70 ml).Methyliodide (10.3 ml; 164 mmol) was added and the solution was cooledto 0° C. Sodium hydride (60% in oil)( 2.07 g; 61.6 mmol) was added inportions and the solution was stirred at roomtemperature for four days.Ethyl acetate (70 ml) and water (60 ml) was added dropwise and thesolvent was removed in vacuo. The crude product was dissolved in water(40 ml) and ether (40 ml). The organic phase was washed with a saturatedaqueous solution of sodium hydrogencarbonate (30 ml). The aqueous phaseswere mixed and 5% aqueous citric acid was added to pH 3. The aqueousphase was extracted with ethylacetate (4×50 ml). The organic phase waswashed with water (2×40 ml), an aqueous solution of sodium thiosulfate(5%; 40 ml), water (40 ml), dried over MgSO₄ and the solvent was removedin vacuo. The residue was dissolved in ethylacetate (45 ml) and washedwith an aqueous solution of sodium hydrogensulfate (10%; 3×30 ml), driedover MgSO₄ and and concentrated in vacuo to give 4.00 g of(2E)-5-(N-(tert Butoxycarbonyl)N-methylamino)-5-methylhex-2-enoic acid.

[1059]¹H-NMR (CDCl₃) d 1.38 (s, 6H), 1.45 (s, 9H ); 2.80 (d, 2H); 2.85(s, 3H); 5.88 (d, 1H); 7.01 (q, 1H).

[1060] The title compound was prepared analogously to example 1.5-Methylamino-5-methylhex-2-enoic acid was incorporated instead of5-amino-5-methylhex-2-enoic acid.

[1061]¹H-NMR :(CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 3H;1.30 (s, 3H); 2.28 (d, 3H); 2.52 (s, 3H); 2.72 (s, 3H); 2.99 (d, 3H);5.69 (dd, 1H); 5.81 (dd, 1H); 6.13 (d, 1H).

[1062] PDMS: m/z 544.4 (M+H)⁺

[1063] HPLC: r_(t)=31.3 min (A1).

Example 64

[1064] (2E)-5Amino-3, 5-dimethylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[1065] The title compound was prepared analogously to example 1.2-thienylalanine was substituted for phenylalanine and5-amino-3,5-dimethylhex-2-enoic acid was substituted for5-amino-5-methylhex-2-enoic acid.

[1066]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.24 (s, 3H);1.25 (s, 3H); 1.76 (s, 2H); 2.32 (s, 3H); 2.76 (d, 3H); 2.99 (s, 3H);5.65 (dd, 1H); 5.76 (s, 1H); 5.90 (dd, 1H)

[1067] HPLC: R_(t)=31.45 min.

[1068] PDMS: m/z 549.7 (M+H)⁺

Example 65

[1069] 5-Amino-5-methyl-hex-2-enoic acid((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(3,4-difluorophenyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide.

[1070] This compound was prepared analogously to example 1.2-(3,4-difluorophenyl)-alanine was substituted for phenylalanine.

[1071]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 1.01 (t, 3H);1.10 (s, 6H); 2.74 (s, 3H); 3.04 (s, 3H); 5.08 (dd, 1H); 5.56 (dd, 1H);6.07 (d, 1H).

[1072] HPLC: r_(t)=32.9 min. (A1)

[1073] PDMS: m/z 610.3 (M+H)⁺

Example 66

[1074] 5-Amino-3,5-dimethylhex-2-enoic AcidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide.

[1075] The title compound was prepared analogously to example 1.N-Tert-Butoxycarbonyl-N-methyl-D-biphenylalanin was substituted forN-tert-butoxycarbonyl-N-methyl-D-phenylalanin in step E.

[1076] (2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid wassubstituted for (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoicacid in step I.

[1077]¹H-NMR (CDCl₃) (selected peaks for major rotamer) d 1.25 (s, 3H);1.28 (s, 3H); 1.57 (s, 3H); 2.32 (s, 3H); 2.73 (d, 3H); 2.94 (s, 3H);5.34 (dd, 1H); 5.45 (dd, 1H); 5.75 (s, 1H).

[1078] HPLC: r_(t)±35.37 min (Method A1)

[1079] PDMS: m/z =569.7 (M+H)⁺

Example 67

[1080] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[1081] This compound was prepared analogously to example 1.N-tert-Butoxycarbonyl-N-methyl-D-4-iodophenylalanine was substituted forN-tert-butoxycarbonyl-N-methyl-D-phenylalanin in step E.

[1082]¹H-NMR (CDCl₃)(selected peaks for major rotamer) d 1.15 (s, 6H);2.09 (d, 3H); 2.69 (s, 3H); 2.70 (s, 3H); 5.24 (dd, 1H); 5.90 (dd, 1H);6.18 (d, 1H).

[1083] HPLC: r_(t)=35,25 min (Method A1)

[1084] PDMS: m/z =655.7 (M+H)⁺

Example 68

[1085] (2E)-5-Methyl-5-methylaminohex-2-enoic AcidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[1086] This compound was prepared analogously to example 1.N-Tert-butoxycarbonyl-N-methyl-D-4-iodophenylalanin was substituted forN-tert-butoxycarbonyl-N-methyl-D-phenylalanin in step E. (2E)-5-(N-(tertButoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid was substitutedfor (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid in stepI.

[1087]¹H-NMR: (CDCl₃)(selected peaks for major rotamer) d 1 .17 (s, 6H);2.07 (d, 3H); 2.39 (s, 3H); 2.71 (s, 6H); 2.92 (s, 3H); 5.25 (dd, 1H);5.90 (dd, 1H); 6.20 (d, 1H).

[1088] HPLC: r_(t)=35.38 min (Method A1)

[1089] PDMS; m/z =668.9 (M+H)⁺

Example 69

[1090] (2E) 5-Methyl-5-amino-5-methylhex-2-enoicAcid-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thien-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide.

[1091] This compound was prepared analogously to example 1.2-thienyl-alanine was substituted for phenylalanine and5-methyl-5-methylaminohex-2-enoic acid was substituted for5-amino-3,5-dimethylhex-2-enoic acid.

[1092]¹H-NMR (CDCl₃): (selected peaks for major rotamer) d 1.25 (s, 3H);1.28 (s, 3H); 2.26 (d, 3H); 2.68 (s, 3H); 2.95 (s, 3H); 3.06 (s, 3H);5.25 (dd, 1H); 5.89 (dd, 1H); 6.22 (d, 1H).

[1093] HPLC: r_(t)=30.4 min.

[1094] PDMS: m/z 549.2 (M+H)⁺

Example 70

[1095](2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide

[1096] (2R)-2-(Formylamino)-3-(2thienyl)propionic Acid

[1097] (2R)-2-Amino-3-(2-thienyl)propionic acid (5.00 g, 29.2 mmol) wasdissolved in formic acid (50 ml). The solution was cooled to 0° C.Acetic acid anhydride (20 ml) was added dropwise. The reaction mixturewas stirred for 16 h, while it was warming up to room temperature. Itwas cooled to 0° C. Water (20 ml) was added dropwise. The solution waswarmed to room temperature. The solvent was is removed in vacuo. Theresiude was suspended in ethyl acetate (20 ml). The precipitation wasfiltered off, collected, and dried in vacuo, to give 3.60 g of crude(2R)-2-(formylamino)-3-(2-thienyl)propionic acid, which was used for thefollowing step.

[1098]¹H-NMR (DMSO d₆): d 3.05 and 3.15 (both ABX, together 1H); 3.30and 3.55 (m and ABX, together 1H); 4.30 and 4.55 (both m, together I H);6.90 (m, 1H); 6.95 (m, 1H); 7.35 (d, 1H); 8.03 (s, 1H); 8.40 (d, 1H);12.92 (br, 1H).

[1099] (2R)-2-Methylamino-3-(2-thienyl)propan-1-ol

[1100] A solution of (2R)-2-(formylamino)-3-(2-thienyl)propionic acid(3.58 g, 18.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to asuspension of sodium borohydride in tetrahydrofuran (50 ml), which wascooled to 7-12° C. (inside temperature). After the addition wasfinished, a solution of iodine (4.57 9, 18.0 mmol) in tetrahydrofuran(100 ml) was added dropwise. The reaction mixture was heated to refluxfor 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise.The solvent was removed in vacuo. The residue was dissolved in a freshlyprepared 20% aqueous sodium hydroxide solution (200 ml). The aqueousphase was extracted with tert-butyl methyl ether (4×150 ml). Thecombined organic layers were dried over magnesium sulfate. The solventwas removed in vacuo to give 3.26 g of crude(2R)-2-methylamino-3-(2-thienyl)propan-1-ol, which was used for thefollowing step.

[1101]¹H-NMR (DMSO d₆ selected values): d 2.32 (s, 3H); 2.56 (m, 1H);2.84 (m, 2H); 3,30 (m, 2H); 6.85 (m, 1H); 6.93 (m, 1H); 7.28 (d, 1H).

[1102] N-((1R)-1-(Hydroxymethyl)-2-(2-thienyl)ethyl)-N-methylcarbamicAcid Tert-Butyl Ester

[1103] A solution of di-tert-butyldicarbonate (4.97 g, 22.8 mmol) intetrahydrofuran (20 ml) was added dropwise to a solution of(2R)-2-methylamino-3-(2-thienyl)propan-1-ol in 1 N aqueous sodiumhydroxide solution (19 ml) and tetrahydrofuran (20 ml). The reacionmixture was stirred at room temperature for 16 h. It was diluted withwater (100 ml) and extracted with ethyl acetate (3×150 ml). The combinedorganic layers were washed with saturated sodium hydrogen carbonatesolution (200 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (220 g), using ethyl acetate/heptane 1:1 as eluent, to give3.85 g of N-((1R)-1-(hydroxymethyl)-2-(2-thienyl)ethyl)-N-methylcarbamicacid tert-butyl ester.

[1104]¹H-NMR (CDCl₃, selected values) d 1.41 (br, 9H); 2.75 (br, 3H);3.05-3.20 (both br, together 2H); 3.75 (br, 2H); 4.10 and 4.27 (both br,together I H); 6.82 (br, 1H); 6.90 (m, 1H); 7.14 (d, 1H).

[1105]N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic AcidTert-Butyl Ester

[1106] A solution of oxalyl chloride (1.81 ml, 20.8 mmol) indichloromethane (180 ml) was cooled to −78° C. A solution ofdimethylsulfoxide (2.15 ml, 27.8 mmol) in dichloromethane (2 ml) wasadded dropwise. The solution was stirred for 15 min at −78° C. Asolution ofN-((1R)-1-(hydroxymethyl)-2-(2-thienyl)ethyl)-N-methylcarbamic acidtert-butyl ester (3.78 g, 13.9 mmol) in dichloromethane (10 ml) wasadded dropwise. The solution was stirred for 20 min at -78° C.Triethylamine (7.71 ml, 55.6 mmol) was added. The solution was stirredfor 5 min at −78° C. and warmed to −35° C. As soon as -35° C. wasreached it was cooled to −78° C. Acetic acid (3.50 ml, 61.2 mmol) wasadded. The solution was warmed to room temperature and was washed withbrine (200 ml). The organic phase was dried over magnesium sulfate. Thesolvent was removed in vacuo. The residue was dissolved in methanol (180ml). 4 A mol (20 g) sieves was added. Acetic acid (5.5 ml, 97.3 mmol)was added. An 8.0 M solution of methylamine in ethanol (5.2 ml, 41.7mmol) was added. Solid sodium cyano borohydride (0.57 g, 9.1 mmol) wasadded. The solution was stirred at room temperature for 1 h, beforeanother portion of solid sodium cyano borohydride (0.57 g, 9.1 mmol) wasadded. The reaction mixture was stirred for 16 h at room temperature andfiltered through a plug of celite. The celite was washed with methanol(150 ml). The solvent of the filtrate was removed in vacuo. The residuewas dissolved in 1 N sodium hydroxide solution (200 ml). The solutionwas extracted with tert-butyl methyl ether (3×100 ml). The combinedorganic layers were dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (150 g), using dichloromethane/methanol/25% aqueous ammonia100:10:1 as eluent, to give 1.72 g ofN-methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acidtert-butyl ester.

[1107]¹H-NMR (CDCl₃, selected values) d 1.32 and 1.42 (both br, together9H); 2.44 (s, 3H); 2.63 (ABX, 1H); 2.70-2.90 (m, 4H); 2.95 and 3.03(both br, together 2H); 4.40 (br, 1H); 6.82 (br, 1H); 6.92 (m, 1H); 7.15(d, 1H).

[1108] MS: 285 [M+1]⁺.

[1109]N-Methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamicAcid Tert-Butyl Ester

[1110]N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acidtert-butyl ester (1.72 g, 6.05 mmol) was dissolved in dichloromethane(30 ml). Triethylamine (0.84 ml, 6.05 mmol) was added. The solution wascooled to −78 ° C. Methanesulfonyl chloride (0.47 ml, 6.05 mmol) wasadded dropwise. The reaction mixture was warmed to room temperature overa period of 3.5 h. It was stirred at room temperature for 16 h. Thereaction mixture was diluted with dichloromethane (100 ml). It waswashed with 10% aqueous sodium hydrogen sulfate solution (200 ml). Theaqueous phase was extracted with dichloromethane (2×50 ml). The combinedorganic layers were washed with saturated sodium hydrogen carbonatesolution (200 ml) and dried over magnesium sulfate. The solvent wasremoved in vacuo. The crude product was purified by flash chromatographyon silica (180 g), using ethyl acetatelheptane 1:1 as eluent, to give1.94 g ofN-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamicacid tert-butyl ester.

[1111]¹H-NMR (CDCl₃) d 1.40 and 1.45 (both s, together 9H); 2.74 and2.80 (s and m, together 6H); 2.91 (s, 3H); 3.06 (m, 3H); 3.57 (m, 1H);4.55 (br, 1H); 6.85 (d, 1H); 6.92 (m, 1H); 7.16 (m, 1H).

[1112]N-Methyl-N-((2R)-2-(methylamino)-3-(2-thienyl)propyl)methanesulfonamide

[1113] A solution of ofN-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamicacid tert-butyl ester (1.87 g, 7.12 mmol) in dichloromethane (7 ml) wascooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reactionmixture was stirred for 45 min at 0° C. Dichloromethane (10 ml) wasadded. A saturated aqueous solution of sodium hydrogen carbonate (10 ml)was added. Solid sodium hydrogen carbonate was added until pH 7.Water(100 ml) was added, until a clear solution was obtained. The phases wereseparated. The aqueous phase was extracted with dichloromethane (2×50ml). The combined organic phases were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (120 g), using dichloromethane/methanol/25%aqueous ammonia as eluent, to give 1.24 g ofN-methyl-N-((2R)-2-(methylamino)-3-(2-thienyl)propyl)methanesulfonamide.

[1114]¹H-NMR (CDCl₃) d 2.47 (s, 3H); 2.81 (s, 3H); 2.88 (s, 3H);2.90-3.10 (m, 4H); 3.22 (dd, 1H); 6.86 (m, 1H); 6.95 (m, 1H); 7.19 (m,1H).

[1115]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsufonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicAcid Tert-Butyl Ester

[1116] (1.46 g, 4.42 mmol) was dissolved in N,N-dimethylformamide (5 ml)and dichloromethane (5 ml). 1-Hydroxy-7-azabenzotridazole (0.60 g, 4.42mmol) was added. The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.85 g,4.42 mmol) was added. The reaction mixture was stirred for 20 min at 0°C. A solution ofN-methyl-N-((2R)-2-(methylamino)-3-(2-thienyl)propyl)methanesulfonamide(1.16 g, 4.42 mmol) in dichloromethane (5 ml) and ethyldiisopropylamine(0.76 ml, 4.42 mmol) were added successively. The solution was stirredfor 16 h, while it was warming up to room temperature. It was dilutedwith ethyl acetate (90 ml) and washed with 10% aqueous sodium hydrogensulfate solution (100 ml). The aqueous phase was extracted with ethylacetate (2×30 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (100 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (240 g), using ethylacetate/heptane 2:1 as eluent, to give 2.05 g ofN-Methyl-N-((1R)-1-(N-methyl-N((1R)-1-((N-methyl-N-(methylsufonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester.

[1117]¹H-NMR (CDCl₃, selected values) d 1.09 and 1.33 (both s, together9H); 5.05 and 5.37 (both dd, together 1H).

[1118](2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide

[1119] A solution of ofN-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsufonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (1.94 g, 3.37 mmol) in dichloromethane (7 ml) wascooled to 0° C. Trifluoroacetic acid (7 ml) was added. The reactionmixture was stirred for 45 min at 0° C. A saturated aqueous solution ofsodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogencarbonate was added until pH 7. Water (100 ml) was added, until a clearsolution was obtained. The phases were separated. The aqueous solutionwas extracted with dichloromethane (2×50 ml). The combined organiclayers were dried over magnesium sulfate. The solvent was removed invacuo. The crude product was purified by flash chromatography on silica(200 g), using dichloromethanelmethanol/25% aqueous ammonia as eluent,to give 1.70 g of(2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide.

[1120]¹H-NMR (CDCl₃, selected values) d 2.04 and 2.32 (both s, together3H); 2.61 and 2.65 (both s, together 3H); 2.71 and 2.73 (both s,together 3H); 2.82 and 2.85 (both s, together 3H); 3.68 and 3.75 (botht, together 1H); 5.14 (br, 1H).

[1121]((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsuflonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicAcid Tert-Butyl Ester

[1122] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2enoic acid (158mg, 0.65 mmol) was dissolved in N,N-dimethylformamide (3 ml) anddichloromethane (3 ml). 1-Hydroxy-7-azabenzotriazole was added. Thesolution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (88 mg,0.65 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of(2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamidein dichloromethane (3 ml) and ethyldiisopropylamine (0.12 ml, 0.65 mmol)were added successively. The reaction mixture was stirred for 16 h,while it was warming up to room temperature. It was diluted with ethylacetate (50 ml) and washed with 10% aqueous sodium hydrogen sulfatesolution (50 ml). The aqueous phase was extracted with ethyl acetate(2×50 ml). The organic layers were washed with a saturated aqueoussolution of sodium hydrogen carbonate (100 ml) and dried over magnesiumsulfate. The solvent was removed in vacuo. The crude product waspurified on silica (120 g), using ethyl acetatelheptane 2:1 (250 ml) andsuccessively ethyl acetate/heptane 3:1 as eluent, to give 282 mg of((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsuflonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester.

[1123]¹H-NMR (CDCl₃, selected values) d 1.15-1.35 (m, 6H); 1.40 and 1.69(m and br, together 9H);5.69 and 5.85 (both m, together 1H); 6.06, 6.13,and 6.27 (all d, together 1H).

[1124] A solution of ((3E)-1,1-Dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsuflonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamicacid tert-butyl ester (251 mg, 0.36 mmol) in dichloromethane (3 ml) wascooled to 0° C. Trifluoroacetic acid (3 ml) was added. The solution wasstirred for 50 min at 0° C. A saturated aqueous solution of sodiumhydrogen carbonate (15 ml) was added. Solid sodium hydrogen carbonatewas added until pH 7. Water (70 ml) was added, until a clear solutionwas obtained. The phases were separated. The aqueous phase was extractedwith dichloromethane (3×30 ml). The combined organic layers were 'driedtwo times over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (120 g),using dichloromethane/methanol/25% aqueous ammonia as eluent, to give159 mg of the title compound. The HPLC showed a 20% impurity, which is adiastereoisomere of the title compound.

[1125]¹H-NMR (CDCl₃, selected values) d 1.14 (br, 6H); 5.05 (br, 1H);5.66, 5.77, and 5.85 (all dd, together 1H); 6.08, 6.13 and 6.40 (all dd,together 1H). MS 598.8 [M + 1]⁺; 599.0 [M + 1]⁺, isomeric impurity. HPLC31.22 min (A1); 32.75 min (A1, isomeric impurity); 33.18 min (B1); 34.88min (B1, isomeric impurity).

[1126] For biological testing, the title compound was transferred intoits acetate salt, by liophilization from 0.5 M acetic acid (50 ml).

Example 71

[1127](2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide

[1128] N-Methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamic Acid Tert-Butyl Ester

[1129] At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (2.18 g, 11.4 mmol) was added to a solution of(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid(3.0 g, 11.4 mmol) and 1-hydroxybenzotriazole hydrate (1.54 g, 11.4mmol) in N,N-dimethylformamide (2 ml) and dichloromethane (4 ml). Thereaction mixture was stirred for 15 min at 0° C.2,2,2-Trifluoroethylamine (0.91 ml, 11.4 mmol) and ethyldiisopropylamine(2.0 ml, 11.39 mmol) were added successively. The reaction mixture wasstirred for 16 h, while it was warming up to room temperature. It wasdiluted with ethyl acetate (150 ml) and washed with 10% aqueous sodiumhydrogen sulfate solution (200 ml). The aqueous phase was extracted withethyl acetate (2×30 ml). The combined organic layers were washed withsaturated sodium hydrogen carbonate solution (150 ml) and dried overmagnesium sulfate. The solvent was removed in vacuo. The crude productwas purified by flash chromatography on silica (240 g), using ethylacetate/heptane 1:2 as eluent, to give 3.52 g ofN-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamicacid tert-butyl ester.

[1130]¹H-NMR (CDCl₃): d 1.30 and 1.42 (both br, together 9H); 2.76 (s,3H); 3.04 (m, 1H); 3.35 and 3.48 (both m, together 1H); 3.65 and 3.85(both m, together 1H); is 4.13 (m, 1H); 4.74 and 4.92 (both br, together1H); 5.25 and 6.75 (both br, together 1H); 7.10-7.40 (m, 5H).

[1131] MS: 361.0 [M+1]⁺; 261.0 [M+1−BOC]⁺.

[1132] (2R)-2-Methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide

[1133]N-Methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamicacid tert-butyl ester (3.45 g, 9.57 mmol) was dissolved indichloromethane (8 ml). The solution was cooled to 0° C. Trifluoroaceticacid (8 ml) was added. The reaction mixture was stirred for 45 min at 0°C. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) wasadded. Solid sodium hydrogen carbonate was added until pH 7. Water (100ml) was added, until a clear solution was obtained. The phases wereseparated. The aqueous phase was extracted with dichloromethane (3×30ml). The combined organic layers were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (180 g), using dichloromethane/methanol/25%aqueous ammonia as eluent to give 1.13 g of(2R)-2-methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide.

[1134]¹H-NMR (CDCl₃): d 2.27 (s, 3H); 2.73 (dd, 1H); 3.15-3.35 (m, 2H);3.95 (m, 2H); 7.15-7.40 (m, 5H); 7.70 (br, 1H).

[1135]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicAcid Tert-Butyl Ester

[1136] A solution of(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid (1.35 g, 4.1 mmol) and 1-hydroxy-7-azabenzotriazole (0.56 g, 4.1mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (5 ml) wascooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.79 g, 4.1 mmol) was added. The reaction mixture wasstirred for 15 min at 0° C. A solution of(2R)-2-methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide (1.07g, 4.1 mmol) in dichloromethane (5 ml) was added. Ethyldiisopropylamine(0.71 ml) was added. The reaction mixture was stirred for 16 h, while itwas warming up to room temperature. It was diluted with ethyl acetate(100 ml) and washed with 10% aqueous sodium hydrogen sulfate solution(100 ml). The aqueous phase was extracted with with ethyl acetate (2×50ml). The combined organic layers were washed with saturated sodiumhydrogen carbonate solution (100 ml) and dried over magnesium sulfate.The solvent was removed in vacuo. The crude product was purified byflash chromatography on silica (170 g), using ethyl acetate/heptane 1:2(300 ml), and then ethyl acetatelheptane/dichloromethane 1:1:1 as eluentto give 1.14 g ofN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester.

[1137]¹H-NMR (CDCl₃, selected values): d 1.09 and 1.31 (both s, together9H); 5.00-5.50 (m, together 2H); 7.00-7.80 (m, 12H).

[1138](2R)-2-Methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)propionamide

[1139]N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamicacid tert-butyl ester (1.12 g, 1.97 mmol) was dissolved indichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroaceticacid (6 ml) was added. The reaction mixture was stirred for 45 min at 0°C. A saturated solution of aqueous sodium hydrogen carbonate (30 ml) wasadded. Solid sodium hydrogen carbonate was added until pH 7. Water (100ml) was added until a clear solution was obtained. The phases wereseparated. The aqueous solution was extracted with dichloromethane (2×50ml). The combined organic layers were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified by flashchromatography on silica (90 g), using dichloromethane/methanol/25%aqueous ammonia 100:10:1 as eluent, to give 946 mg of(2R)-2-methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)propionamide.

[1140]¹H-NMR (CDCl₃, selected values): d 1.77, 2.36, 2.65, and 2.91 (alls, together 6H); 4.56 and 5.55 (both dd, together 1H); 6.85-7.90 (m,together 12H).

[1141]((3E)-4-(N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicAcid Tert-Butyl Ester

[1142] (2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (168mg, 0.69 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg, 0.69 mmol) weredissolved in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml).The solution was cooled to 0° C.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (132 mg,0.69 mmol) was added. The reaction mixture was stirred for 15 min at 0°C. A solution of(2R)-2-methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)propionamide(327 mg, 0.69 mmol) in dichloromethane (3 ml) was added.Ethyldiisopropylamine (0.12 ml, 0.69 mmol) was added. The reactionmixture was stirred for 16 h, while it was warming up to roomtemperature. It was diluted with ethyl acetate (50 ml) and washed with10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phasewas extracted with ethyl acetate (2×20 ml). The combined organic layerswere washed with saturated sodium hydrogen carbonate solution (100 ml)and dried over magnesium sulfate. The solvent was removed in vacuo. Thecrude product was purified by flash chromatography on silica (160 g),using ethyl acetate/heptane 1:1 as eluent to give 447 mg of((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester.

[1143]¹H-NMR (CDCl₃, selected values): d 1.20, 1.23, 1.28, and 1.29 (alls, together 15H); 2.55, 2.76, 2.95, and 3.02 (all s, together 6H);7.00-7.85 (m, 12H).

[1144]((3E)-4-(N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamicacid tert-butyl ester (407 mg, 0.58 mmol) was dissolved indichloromethane (4 ml). The solution was cooled to 0° C. Trifluoroaceticacid (4 ml) was added. The reaction mixture was stirred for 45 min at 0°C. A saturated aqueous solution of sodium hydrogen carbonate (5 ml) wasadded. Solid sodium hydrogen carbonate was added until pH 7. Water (100ml) was added, until a clear solution was obtained. The phases wereseparated. The aqueous phase was extracted with dichloromethane (2×20ml). The combined organic layers were dried over magnesium sulfate. Thesolvent was removed in vacuo. The crude product was purified on silica(90 g) using dichloromethane/methanol/25% aqueous ammonia as eluent, togive 251 mg of the title comopund.

[1145]¹H-NMR (CDCl₃, selected values): d 1.00 and 1.13 (both s, together6H); 2.57, 2.77, 2.98, and 3.06 (all s, together 6H); 5.30 (m, 1H); 5.60and 5.87 (both dd, together 1H); 6.04 and 6.05 (both d, together 1H)6.86 (m, 1H).

[1146] MS: 597.0 [M+1]⁺

[1147] HPLC: 35.55 min (A1) 37.87 min (B1).

[1148] For biological testing, the title compound was transferred intoits acetate salt by liophilization from 0.5 M acetic acid (50 ml).

Example 72

[1149] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[1150] This compound was prepared analogously to example 1 usingcyclopropylamine instead of methylamine.

[1151]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 0.43 (m, 4H);1.08 (s, 6H); 2.99 (s, 3H); 5.15 (dd, 1H); 5.57 (dd, 1H); 6.04 (d, 1H).

[1152] HPLC: r_(t)=33.2 min (A1)

[1153] PDMS: m/z 554 (M+H)⁺

Example 73

[1154] (2E)-4-(1-Aminocyclobutyl)but-2-enoic AcidN-((1R)-1-(N-((1R)-2-(3,4-difluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[1155] This compound was prepared analogously to example 1 using(3,4-difluorophenyl)alanine instead of phenylalanine and(2E)-4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid(prepared as in R. Graf, Org Synth. 46, 51 (1966) ) instead of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid.

[1156]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.93 (s, 6H);2.05 (s, 3H); 2.75 (s, 3H); 2.91 (s, 3H); 5.24 (dd, 1H); 5.92 (dd, 1H);6.29 (d, 1H)

[1157] HPLC: r_(t)=33.9 min (A1)

[1158] PDMS: m/z 576 (M+H)⁺

Example 74

[1159] (2E)-4-(1-Aminocyclobutyl)but-2-enoic AcidN-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[1160] This compound was prepared analogously to example 1 usingcyclopropylamine instead of methylamine and and(2E)A4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid(prepared as in R. Graf, Org Synth. 46, 51 (1966) ) instead of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid.

[1161]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 0.45 (m, 4H);2.49 (s, 3H); 2.95 (s, 3H); 5.18 (dd, 1H); 5.78 (dd, 3H); 6.33 (d, 1H)

[1162] HPLC: r_(t)=33.9 min (A1)

[1163] PDMS: m/z 567 (M+H)⁺

Example 75

[1164] (2E) 4-(1-Aminocyclobutyl)-but-2-enoic AcidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide

[1165] This compound was prepared analogously to example 1 usingbiphenylalanine instead of phenylalanine and and(2E)-4-(1-(tert-butoxycarbonylamino)cyclobutyl)but-2-enoic acid(prepared as in R. Graf, Org Synth. 46, 51 (1966) ) instead of(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid.

[1166]¹H-NMR: (CDCl₃) (selected peaks for major rotamer) d 1.98 (m, 6H);2.49 (s, 3H); 2.59 (d, 3H); 2.95 (s, 3H); 5.50 (dd, 1H); 5.78 (dd, 1H);6.18 (d, 1H).

[1167] HPLC: r_(t)=34.9 min (A1)

[1168] PDMS: m/z (M+H)⁺

[1169] LC-MS: 569.0 (m+1)⁺

Example 76

[1170]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide

[1171] The N-Methyl-PAL-Resin (75 mg, 0.045 mmol, load: 0.60) was washedwith 5% diisopropylethylamine in dichloromethane (2×2 mL),dichloromethane (3×2 mL) and dimethylformamide (3×2 mL) and then swelledin dimethylformamide (2 mL). Then2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2thienyl)propionicacid (46 mg, 0.09 mmol) in dimethylformamide (1 mL),0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (15 mg, 0.09 mmol) in dimethylformamide (1mL) and diisopropylethylamine (31 mL, 0.18 mmol) in dimethylformamide (ImL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). Then 20% piperidine indimethylformamide (5 mL) was added and the mixture was shaken for 20min, filtered and washed with dimethylformamide (3×2 mL),dichloromethane (3×2 mL) and dimethylformamide (2 mL). Then2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)3-(2-naphthyl)propionicacid (41 mg, 0.09 mmol) in dimethylformamide (1 mL),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (15 mg, 0.09 mmol) in dimethylformamide (1mL) and diisopropylethylamine (31 ml, 0.18 mmol) in dimethylformamide (1mL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). Then 20% piperidine indimethylformamide (5 mL) was added and the mixture was shaken for 20min, filtered and washed with dimethylformamide (3×2 mL),dichloromethane (3×2 mL) and dimethylformamide (2 mL). Then3-(1-(tert-butoxycarbonylamino)ethyl)-benzoic acid(22 mg, 0.09 mmol) indimethylformamide (1 mL),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (1 mL),1-hydroxy-7-azabenzotriazole (15 mg, 0.09 mmol) in dimethylformamide (1mL) and diisopropylethylamine (31 mL, 0.18 mmol) in dimethylformamide (1mL) were added and the mixture was shaken overnight. The resin wasfiltered and washed with dimethylformamide (3×2 mL), dichloromethane(3×2 mL) and dimethylformamide (2 mL). The resin was cooled to 0° C. and50% trifluoroacetic acid in dichloromethane (4 mL) was added and themixture was shaken for 10 min at 0° C. The resin was filtered and washedwith 50% trifluoroacetic acid in dichloromethane (2×0.5 mL) and thecombined filtrates were concentrated under a stream of nitrogen. Theobtained product was dissolved in acetonitrile/water 1:20 (10 mL) andapplied to a C-18 Sep-Pak Classic® cartridge (0.25 g, purchased fromWaters™), which had been prewashed with acetonitrile (10 mL) and water(10 mL). Then water/trifluoroacetic acid 99.9:0.1 (5 mL), followed bywater/acetonitrile/ trifluoroacetic acid 89.9:20:0.1 (4 mL) was runthrough the Sep-Pak® and the filtrate was discarded. Then the Sep-Pak®was washed with water/acetonitrile/trifluoroacetic acid 64.9:35:0.1 (4mL) and the filtrate was diluted with water (11 mL) and lyophilized to 4mg of the title product.

[1172] HPLC: (A1) R_(t)=31.05 min (B1) R_(t)=33.00 min

[1173] LC-MS: 557.0 (m+1)⁺

Example 77

[1174]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide:

[1175] The title compound was prepared analogously to example 76 with3-(1-(tert-butoxycarbonylamino)methyl)-benzoic acid instead of3-(1-(tert-butoxy-carbonylamino)ethyl)benzoic acid.

[1176] Yield: 5.0 mg

[1177] HPLC: (A1) R_(t)=30.32 min (B1) R_(t)=32.22 min

[1178] LC-MS: 542.8 (m+1)⁺

Example 78

[1179](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide:

[1180] The title example 76 with(2-(tert-butoxycarbonylamino)butoxy)-acetic acid instead of3-(t-(tert-butoxy-carbonylamino)ethyl)benzoic acid.

[1181] Yield: 10.4 mg

[1182] HPLC: (A1) R_(t)=30.13 min (B1) R_(t)=31.98 min

[1183] LC-MS: (m+1)⁺

Example 79

[1184](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide:

[1185] The title compound was prepared analogously to example 76 with(2S)-2-(((carboxy)methoxy)methyl)pyrro-lidin-1-carboxylic acidtert-butyl ester instead of3-(1-(tert-butoxy-carbonylamino)ethyl)benzoic acid.

[1186] Yield: 9.4 mg

[1187] HPLC: (A1) R_(t)=30.07 min (B1) R_(t)=31.88 min

[1188] LC-MS: (m+1)⁺

Example 80

[1189](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide:

[1190] The title compound was prepared analogously to example 76 with(2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetic acid instead of3-(1-(tert-butoxycarbonylamino)ethyl)benzoic acid.

[1191] Yield: 10.5 mg

[1192] HPLC: (A1) R_(t)=29.77 min (B1) R_(t)=31.62 min

[1193] LC-MS: (m+1)⁺

Example 81

[1194]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide:

[1195] The title compound was prepared analogously to example 76 with(2R)-3-(benzo[b]thiophen-3-yl)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1196] Yield: 3.2 mg

[1197] HPLC: (A1) R_(t)=30.62 min (B1) R_(t)=32.57 min

[1198] LC-MS: 563.0 (m+1)⁺

Example 82

[1199]3-(1-Aminomethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide:

[1200] The title compound was prepared analogously to example 77 with(2R)-3-(benzo[b]thiophen-3-yl)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1201] Yield: 2.0 mg

[1202] HPLC: (A1) R_(t)=29.82 min (B1) R_(t)=31.73 min

[1203] LC-MS: 549.0 (m+1)⁺

Example 83

[1204](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1205] The title compound was prepared analogously to example 78with(2R)-3-(benzo[b]thiophen-3-yl)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-5methylamino)-propionic acid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1206] Yield: mg

[1207] HPLC: (A1) R_(t)=min (B1) R_(t) =min

[1208] LC-MS: (m+1)⁺

Example 84

[1209](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1210] The title compound was prepared analogously to example 79 with(2R)-3-(benzo[b]thiophen-3-yl)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1211] Yield: 7.6 mg

[1212] HPLC: (A1) R_(t)=29.42 min (B1) R_(t)=31.23 min

[1213] LC-MS: 557.0 (m+1)⁺

Example 85

[1214] (2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1215] The title compound was prepared analogously to example 80 with(2R)-3-(benzo[b]thiophen-3-yl)-2-(N-(gH-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-propionic acid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1216] Yield: 5.8 mg

[1217] HPLC: (A1) R_(t)=29.22 min (B1) R_(t)=31.00 min

[1218] LC-MS: 544.8 (m+1)⁺

Example 86

[1219] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide:

[1220] The title compound was prepared analogously to example 85 with(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid instead of(2-(tert-butoxycarbonylamino)2-methylpropoxy)acetic acid.

[1221] Yield: 2.0 mg

[1222] HPLC: (A1) R_(t)=29.62 min (B1) R_(t)=31.50 min.

[1223] LC-MS: 541.2 (m+1)⁺

Example 87

[1224]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1225] The title compound was prepared analogously to example 76 with(2R)-2-((9H-fluoren-9-ylmethoxy-carbamoyl)methylamino)-3-benzyloxypropionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1226] Yield: 10.0 mg

[1227] HPLC: (A1) R_(t)=28.85 min (B1) R_(t)=30.67 ml

[1228] LC-MS: (m+1)⁺

Example 88

[1229]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1230] The title compound was prepared analogously to example 77 with(2R)-2-((9H-fluoren-9-ylmethoxy-carbamoyl)methylamino)-3-benzyloxypropionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1231] Yield: 8.4 mg

[1232] HPLC: (A1) R_(t)=30.45 min (B1) R_(t)=30.43 min

[1233] LC-MS: 522.8 (m+1)⁺

Example 89

[1234](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide:

[1235] The title compound was prepared analogously to example 78 with(2R)-2-((9H-fluoren-9-ylmethoxy-carbamoyl)methylamino)-3-benzyloxypropionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1236] Yield: 9.8 mg

[1237] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1238] LC-MS: 519.0 (m+1)⁺

Example 90

[1239](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide:

[1240] The title compound was prepared analogously to example 79 with(2R)-2-((9H-fluoren-9-ylmethoxy-carbamoyl)methylamino)-3-benzyloxypropionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1241] Yield: 11.1 mg

[1242] HPLC: (A1) R_(t)=27.77 min (B1) R_(t)=29.40 min

[1243] LC-MS: (m+1)⁺

Example 91

[1244](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide:

[1245] The title compound was prepared analogously to example 80 with(2R)-2-((9H-fluoren-9-ylmethoxy-carbamoyl)methylamino)-3-benzyloxypropionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1246] Yield: 11.9 mg

[1247] HPLC: (A1) R_(t)=28.50 min (B1) R_(t)=29.23 min

[1248] LC-MS: 519.0 (m+1)⁺

Example 92

[1249] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide:

[1250] The title compound was prepared analogously to example 91 with(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid instead of(2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetic acid.

[1251] Yield: 1.5 mg

[1252] HPLC: (A1) R_(t)=28.03 min (B1) R_(t)=29.77 min

[1253] LC-MS: (m+1)⁺

Example 93

[1254]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1255] The title compound was prepared analogously to example 76 with(2R)-3-(biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1256] Yield: 2.0 mg

[1257] HPLC: (A1) R_(t)=34.58 min (B1) R_(t)=36.67 min

[1258] LC-MS: (m+1)⁺

Example 94

[1259]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1260] The title compound was prepared analogously to example 77 with(2R)-3-(biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1261] Yield: 12.3 mg

[1262] HPLC: (A1) R_(t)=33.92 min (B1) R_(t)=35.97 min

[1263] LC-MS: (m+1)⁺

Example 95

[1264](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1265] The title compound was prepared analogously to example 78 with(2R)-3-(biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1266] Yield: 13.5 mg

[1267] HPLC: (A1) R_(t)=33.57 min (B1) R_(t)=34.47 min

[1268] LC-MS: (m+1)⁺

Example 96

[1269] (2R) -2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1270] The title compound was prepared analogously to example 79 with(2R)-3-(biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1271] Yield: 11.0 mg

[1272] HPLC: (A1) R_(t)=33.30 min (B1) R_(t)=35.24 min

[1273] LC-MS: (m+1)⁺

Example 97

[1274](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1275] The title compound was prepared analogously to example 80 with(2R)-3-(biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid instead of2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionicacid.

[1276] Yield: 13.1 mg

[1277] HPLC: (A1) R_(t)=27.68 min (B1) R_(t)=30.22 min

[1278] LC-MS: (m+1)⁺

Example 98

[1279] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide:

[1280] The title example 997 with(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid instead of(2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetic acid.

[1281] Yield: 13.1 mg

[1282] HPLC: (A1) R_(t)=28.48 min (B1) R_(t)=30.03 min

[1283] LC-MS: (m+1)⁺

Example 99

[1284]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide:

[1285] The title compound was prepared analogously to example 76 with(2R)-2-propionic acid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionic acid.

[1286] Yield: 5.0 mg

[1287] HPLC: (A1) R_(t)=32.00 min (B1) R_(t)=33.98 min

[1288] LC-MS: 568.8 (m+1)⁺

Example 100

[1289]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide:

[1290] The title compound was prepared analogously to example 77 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1291] Yield: 2.8 mg

[1292] HPLC: (A1) R,=31.30 min (B1) R_(t)=33.23 min

[1293] LC-MS: 555.0 (m+1)⁺

Example 101

[1294](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide:

[1295] The title compound was prepared analogously to example 78 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1296] Yield: 10.1 mg

[1297] HPLC: (A1) R_(t)=31.25 min (B1) R_(t)=33.03 min

[1298] LC-MS: (m+1)⁺

Example 102

[1299](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2(2fluorophenyl)ethyl)-3-(2-naphthyl)propionamide:

[1300] The title compound was prepared analogously to example 79 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1301] Yield: 12.0mg

[1302] HPLC: (A1) R_(t)=31.90 min (B1) R_(t)=32.73 min

[1303] LC-MS: 563.0 (m+1)⁺

Example 103

[1304](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propion-amide:

[1305] The title compound was prepared analogously to example 80 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1306] Yield: 11.5 mg

[1307] HPLC: (A1) R_(t)=30.83 min (B1) R_(t)=32.63 min

[1308] LC-MS: 551.0 (m+1)⁺

Example 104

[1309]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide:

[1310] The title compound was prepared analogously to example 81 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1311] Yield: 3.6 mg

[1312] HPLC: (A1) R_(t)=31.60 min (B1) R_(t)=33.57 min

[1313] LC-MS: 575.0 (m+1)⁺

Example 105

[1314]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide:

[1315] The title compound was prepared analogously to example 82 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1316] Yield: 3.3 mg

[1317] HPLC: (A1) R_(t)=30.82 min (B1) R=32.77 min

[1318] LC-MS: 561.0 (m+1)⁺

Example 106

[1319](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1320] The title compound was prepared analogously to example 83 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1321] Yield: 10.5 mg

[1322] HPLC: (A1) R_(t)=30.62 min (B1) R_(t)=32.45 min

[1323] LC-MS: 557.0 (m+1)⁺

Example 107

[1324](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1325] The title compound was prepared analogously to example 84 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1326] Yield: 7.0 mg

[1327] HPLC: (A1) R_(t)=30.47 min (B1) R_(t)=32.30 min

[1328] LC-MS: 569.0 (m+1)⁺

Example 108

[1329](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide.

[1330] The title compound was prepared analogously to example 85 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1331] Yield: 7.5 mg

[1332] HPLC: (A1) R_(t)=30.33 min (B1) R_(t)=32.1 0 min

[1333] LC-MS: 557.0 (m+1)⁺

Example 109

[1334]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl))-2-(benzyloxy)ethyl)benzamide:

[1335] The title compound was prepared analogously to example 87 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1336] Yield: 4.6 mg

[1337] HPLC: (A1) R_(t)=31.07 min (B1) R_(t)=32.97 min

[1338] LC-MS: 549.0 (m+1)⁺

Example 110

[1339]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-l(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1340] The title compound was prepared analogously to example 88 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1341] Yield: 5.2 mg

[1342] HPLC: (A1) R_(t)=30.25 min (B1) R_(t)=32.10 min

[1343] LC-MS: 535.2 (m+1)⁺

Example 111

[1344](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide:

[1345] The title compound was prepared analogously to example 89 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1346] Yield: 23.6 mg

[1347] HPLC: (A1) R_(t)=29.32 min (B1) R_(t)=30.97 min

[1348] LC-MS: (m+1)⁺

Example 112

[1349](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3(benzyloxy)propionamide:

[1350] The title compound was prepared analogously to example 90 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1351] Yield: 26.0 mg

[1352] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1353] LC-MS: 543.2 (m+1)⁺

Example 113

[1354](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide:

[1355] The title compound was prepared analogously to example 91 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3(2fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1356] Yield: 20.1 mg

[1357] HPLC: (A1) R_(t)=30.17 min (B1) R_(t)=30.77 min

[1358] LC-MS: 531.0 (m+1)⁺

Example 114

[1359]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1360] The title compound was prepared analogously to example 93 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1361] Yield: 10.0 mg

[1362] HPLC: (A1) R_(t)=35.40 min (B1) R_(t)=37.58 min

[1363] LC-MS: 594.8 (m+1)⁺

Example 115

[1364]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1365] The title compound was prepared analogously to example 94 with(2R)-2-(((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1366] Yield: 6.6 mg

[1367] HPLC: (A1) R_(t)=34.70 min (B1) R_(t)=36.08 min

[1368] LC-MS: 581.0 (m+1)⁺

Example 116

[1369](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1370] The title compound was prepared analogously to example 95 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3(2fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1371] Yield: 23.3 mg

[1372] HPLC: (A1) R_(t)=34.13 min (B1) R_(t)=36.08 min

[1373] LC-MS: (m+1)⁺

Example 117

[1374](2R)-2-N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1375] The title compound was prepared analogously to example 96 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1376] Yield: 20.5 mg

[1377] HPLC: (A1) R_(t)=27.65 min (B1) R_(t)=30.18 min

[1378] LC-MS: (m+1)⁺

Example 118

[1379](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1380] The title compound was prepared analogously to example 97 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1381] Yield: 12.2 mg

[1382] HPLC: (A1) R_(t)=34.32 min (B1) R_(t)=36.13 min

[1383] LC-MS: 577.0 (m+1)⁺

Example 119

[1384] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide:

[1385] The title compound was prepared analogously to example 98 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(2-fluorophenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1386] Yield: 5.1 mg

[1387] HPLC: (A1) R_(t)=27.68 min (B1) R_(t)=30.20 min

[1388] LC-MS: (m+1)⁺

Example 120

[1389]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide:

[1390] The title compound was prepared analogously to example 81 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1391] Yield: 4.6 mg

[1392] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1393] LC-MS: 557.0 (m+1)⁺

Example 121

[1394]3-Aminomethyl-N-methyl-N((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide:

[1395] The title compound was prepared analogously to example 82 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1396] Yield: 3.1 mg

[1397] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1398] LC-MS: 542.8 (m+1)⁺

Example 122

[1399](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1400] The title compound was prepared analogously to example 83 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1401] Yield: 1.2 mg

[1402] HPLC: (A1) R_(t)=30.48 min (B1) R_(t)=min

[1403] LC-MS: 539.2 (m+1)⁺

Example 123

[1404](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propion-amide:

[1405] The title compound was prepared analogously to example 84 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1406] Yield: 2.9 mg

[1407] HPLC: (A1) R_(t)=30.47 min (B1) R_(t)=min

[1408] LC-MS: 550.8 (m+1)⁺

Example 124

[1409](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1410] The title compound was prepared analogously to example 85 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1411] Yield: 3.3 mg

[1412] HPLC: (A1) R_(t)=30.18 min (B1) R_(t)=min

[1413] LC-MS: 539.2 (m+1)⁺

Example 125

[1414] (2E)-5-Amino-5-methylhex-2-enoic Acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzob]thiophen-3-yl)ethyl)amide:

[1415] The title compound was prepared analogously to example 86 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1416] Yield: 1.1 mg

[1417] HPLC: (A1) R_(t)=30.57 min (B1) R_(t)=min

[1418] LC-MS: 535.2 (m+1)⁺

Example 126

[1419]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1420] The title compound was prepared analogously to example 87 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1421] Yield: 15.9 mg

[1422] HPLC: (A1) R_(t)=30.87 min (B1) R_(t)=32.50 min

[1423] LC-MS: 531.2 (m+1)⁺

Example 127

[1424]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1425] The title compound was prepared analogously to example 88 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1426] Yield: 13.2 mg

[1427] HPLC: (A1) R_(t)=30.02 min (B1) R_(t)=31.65 min

[1428] LC-MS: 517.0 (m+1)⁺

Example 128

[1429](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide:

[1430] The title compound was prepared analogously to example 89 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)N-methylamino)-3phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)N-methylamino)-3(2-thienyl)propionicacid.

[1431] Yield: 14.7 mg

[1432] HPLC: (A1) R_(t)=29.38 min (B1) R_(t)=30.85 min

[1433] LC-MS: 513.2 (m+1)⁺

Example 129

[1434](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide:

[1435] The title compound was prepared analogously to example 90 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1436] Yield: 17.9 mg

[1437] HPLC: (A1) R_(t)=29.00 min (B1) R_(t)=30.45min

[1438] LC-MS: 525.0 (m+1)⁺

Example 130

[1439] (2R)-2-(N((2Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide:

[1440] The title compound was prepared analogously to example 91 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1441] Yield: 16.5 mg

[1442] HPLC: (A1) R_(t)=29.15 min (B1) R_(t)=30.57 min

[1443] LC-MS: 513.2 (m+1)⁺

Example 131

[1444]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1445] The title compound was prepared analogously to example 93 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1446] Yield: 7.5 mg

[1447] HPLC: (A1) R_(t)=34.63 min (B1) R_(t)=min

[1448] LC-MS: (m+1)⁺

Example 132

[1449]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1450] The title compound was prepared analogously to example 94 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1451] Yield: 9.5 mg

[1452] HPLC: (A1) R_(t)=35.25 min (B1) R_(t)=36.93 min

[1453] LC-MS: (m+1)⁺

Example 133

[1454](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide:

[1455] The title compound was prepared analogously to example 95 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1456] Yield: 13.3 mg

[1457] HPLC: (A1) R_(t)=34.30 min (B1) R_(t)=36.1 0 min

[1458] LC-MS: 559.0 (m+1)⁺

Example 134

[1459](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide:

[1460] The title compound was prepared analogously to example 96 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1461] Yield: 20.9 mg

[1462] HPLC: (A1) R_(t)=34.47 min (B1) R_(t)=36.17 min

[1463] LC-MS: 571.0 (m+1)⁺

Example 135

[1464](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide:

[1465] The title compound was prepared analogously to example 97 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-phenylpropionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid.

[1466] Yield: 25.4 mg

[1467] HPLC: (A1) R_(t)=34.05 min (B1) R_(t)=35.78 min

[1468] LC-MS: 559.0 (m+1)⁺

Example 136

[1469]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide:

[1470] The title compound was prepared analogously to example 76 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1471] Yield: 8.3 mg

[1472] HPLC: (A1) R_(t)=31.32 min (B1) R_(t)=32.92 min

[1473] LC-MS: 580.8 (m+1)⁺

Example 137

[1474]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide:

[1475] The title compound was prepared analogously to example 77 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1476] Yield: 4.1 mg

[1477] HPLC: (A1) R_(t)=30.62 min (B1) R_(t)=min

[1478] LC-MS: 566.8 (m+1)⁺

Example 138

[1479](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide:

[1480] The title compound was prepared analogously to example 78 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1481] Yield: 18.0 mg

[1482] HPLC: (A1) R_(t)=30.78 min (B1) R_(t)=32.27 m:

[1483] LC-MS: 563.2 (m+1)⁺

Example 139

[1484](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)-propionamide:

[1485] The title compound was prepared analogously to example 79 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1486] Yield: 24.0 mg

[1487] HPLC: (A1) R_(t)=30.85 min (B1) R_(t)=32.40 min

[1488] LC-MS: 574.8 (m+1)⁺

Example 140

[1489](2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide:

[1490] The title compound was prepared analogously to example 80 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1491] Yield: 15.6 mg

[1492] HPLC: (A1) R_(t)=30.37 min (B1) R_(t)=31.90 min

[1493] LC-MS: 563.2 (m+.)⁺

Example 141

[1494] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(2-naphthyl)-ethyl)amide:

[1495] The title compound was prepared analogously to example 140 with(2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid instead of(2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetic acid.

[1496] Yield: 2.9 mg

[1497] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1498] LC-MS: 559.0 (m+1)⁺

Example 142

[1499] 3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((seR)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2(benzo[b]thiophen-3-yl)ethyl)-benzamide:

[1500] The title compound was prepared analogously to example 81 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)propionic acid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1501] Yield: 3.4 mg

[1502] HPLC: (A1) R_(t)=30.90 min (B1)R_(t)=min

[1503] LC-MS: 586.8 (m+1)⁺

Example 143

[1504]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide:

[1505] The title compound was prepared analogously to example 82 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1506] Yield: 5.5 mg

[1507] HPLC: (A1) R_(t)=30.15 min (B1) R_(t)=min

[1508] LC-MS: 573.0 (m+i)⁺

Example 144

[1509](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1510] The title compound was prepared analogously to example 83 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1511] Yield: 7.5 mg

[1512] HPLC: (A1) R_(t)=30.18 min (l) R_(t)=min

[1513] LC-MS: 569.0 (m+1)⁺

Example 145

[1514] (2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1515] The title compound was prepared analogously to example 84 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1516] Yield: 10.5 mg

[1517] HPLC: (A1) R_(t)=30.20 min (B1) R_(t)=min

[1518] LC-MS: 581.0 (m+1)⁺

Example 146

[1519](2R)-2-(N-((2Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide:

[1520] The title compound was prepared analogously to example 85 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1521] Yield: 9.9 mg

[1522] HPLC: (A1) R_(t)=29.87 min (B1) R_(t)=min

[1523] LC-MS: 569.0 (m+1)⁺

Example 147

[1524] (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide:

[1525] The title compound was prepared analogously to example 86 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1526] Yield: 4.0 mg

[1527] HPLC: (A1) R_(t)=30.42 min (B1) R_(t)=min

[1528] LC-MS: (m+1)⁺

Example 148

[1529]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1530] The title compound was prepared analogously to example 87 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1531] Yield: 6.1 mg

[1532] HPLC: (A1) R_(t)=30.82 min (B1) R_(t)=min

[1533] LC-MS: 561.2 (m+1)⁺

Example 149

[1534]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide:

[1535] The title compound was prepared analogously to example 88 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1536] Yield: 7.3 mg

[1537] HPLC: (A1) R_(t)=36.23 min (B1) R_(t)=min

[1538] LC-MS: 547.0 (m+1)⁺

Example 150

[1539](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide:

[1540] The title compound was prepared analogously to example 89 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2thienyl)-propionic acid.

[1541] Yield: 2.4 mg

[1542] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1543] LC-MS: (m+1)⁺

Example 151

[1544](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide:

[1545] The title compound was prepared analogously to example 90 with(2R)-2-(N-propionic acid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2thienyl)propionicacid.

[1546] Yield: 19.0 mg

[1547] HPLC: (A1) R_(t)=28.65 min (B,) R_(t)=30.02 min

[1548] LC-MS: 555.0 (m+1)⁺

Example 152

[1549](2R)-2-(N-((2_Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide:

[1550] The title compound was prepared analogously to example 91 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1551] Yield: 20.5 mg

[1552] HPLC: (A1) R_(t)=28.80 min (B1) R_(t)=30.17 min

[1553] LC-MS: 543.2 (m+1)⁺

Example 153

[1554] (2E)-5-Amino-5-methylhex-2-enoic AcidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide:

[1555] The title compound was prepared analogously to example 92 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1556] Yield: 4.0 mg

[1557] HPLC: (A1) R_(t)=28.37 min (B1)R_(t)=min

[1558] LC-MS: 539.2 (m+1)⁺

Example 154

[1559]3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(biphen-4-yl)ethyl)benzamide:

[1560] The title compound was prepared analogously to example 93 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1561] Yield: 8.2 mg

[1562] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1563] LC-MS: 607.0 (m+1)⁺

Example 155

[1564]3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide:

[1565] The title compound was prepared analogously to example 94 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1566] Yield: 7.2 mg

[1567] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1568] LC-MS: 593.2 (m+1)⁺

Example 156

[1569](2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1570] The title compound was prepared analogously to example 95 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1571] Yield: 6.0 mg

[1572] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1573] LC-MS: 589.2 (m+1)⁺

Example 157

[1574](2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide:

[1575] The title compound was prepared analogously to example 96 with(2R)-2-(N-((9H-fluoren-9-yl)methoxy-carbonyl)-N-methylamino)-3-(4-methoxyphenyl)-propionicacid instead of(2R)-2-(N-(9H-fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)-propionicacid.

[1576] Yield: 10.0 mg

[1577] HPLC: (A1) R_(t)=min (B1) R_(t)=min

[1578] LC-MS: 601.0 (m+1)⁺

[1579] General Procedure for Example 158-533

[1580] The following 376 compounds were prepared as single entities byparallel synthesis on a solid support using an Fmoc strategy on anAdvanced ChemTech Model 384 HTS employing HATU/HOAt(0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate/1-hydroxy-7-azabenzotriazole) mediated amidecouplingin dimethylformamide (DMF) according to a protocol known for thoseskilled in the art. The compounds were prepared sequentially accordingto the following equation

Resin-[Building block 1]→Resin-[Building block 1]-[Building block2]→Resin-[Building block 1]-[Building block 2]-[Building block3]→Resin-[Building block 1]-[Building block 2]-[Building block3]-[Building block 4]

[1581] and were simultaneously deprotected and cleaved from the resinwith 50% trifluoroacetic acid (TFA) in dichloromethane (DCM) to give thedesired compounds as individual entities according to the followingformula

[Building block 4]-[Building block 3]-[Building block 2]-[Building block1].

[1582] The starting resins were all prepared separately by reductiveamination of [Building block 1] and a5-(4-formyl-3,5-dimethoxyphenoxy)valerate resin as described in Example44 for N-Me-PAL.

[1583] The substitution capacities of the resins were 0.5-0.7 mmol/gdetermined by UV monitoring of the deprotection of the Fmoc protectiongroup.

[1584] All 376 compounds are based on a scaffold and four varying groupsaccording to the following formula, which is included in general formulaI:

[1585] The 376 compounds were prepared as three separate libraries basedon total combination of four selected building blocks (see example158-253, example 254-353 and example 354-533) and prepared analogouslyto the procedure described in Example 158.

[1586] The following resins, here depicted as Resin-[Building block 1]were used:

[1587] Resins

[1588] Name: N-Me-PAL (described in Example 44)

[1589] Name: N-PhenethylPAL (prepared analogously to N-Me-PAL)

[1590] Name: N-(4-Pyridyl)ethyl-PAL (prepared analogously to N-Me-PAL)

[1591] Name: N-((S)-2-Hydroxypropyl)PAL (prepared analogously toN-Me-PAL)

[1592] Name: N-(2,2-Dimethyl-3-hydroxypropyl)-PAL (prepared analogouslyto N-Me-PAL)

[1593] Name: N((1-Methylpyrrolidin-2-yl)ethyl)-PAL (prepared analogouslyto N-Me-PAL)

[1594] The following building blocks were used:

[1595] Building Block 1

[1596] Name: Methylamine

[1597] Name: Phenethylamine

[1598] Name: 2-(4-pyridyl)ethylamine

[1599] Name: (S)-2-Hydroxypropylamine

[1600] Name: 2,2-Dimethyl-3hydroxypropylamine

[1601] Name: 2-(1-Methylpyrrolidine-2-yl)ethylamine

[1602] Building Block 2

[1603] Name:(2R)-2-[N-(9H-Fluoren-9-yl)methoxycarbonyl)-N-methylamino]-3-(3,4-difluorophenyl)propionic acid Abbreviation:Fmoc-N-Me-D-Phe(3,4-F,F)-OH

[1604] Abbreviation: Fmoc-N-Me-D-Phe-OH

[1605] Name:(2R)-2-(N-(9H-Fluoren-9-ylmethoxycarbonyl)-N-methylamino)-3-(2-thienyl)propionicacid

[1606] Abbreviation: Fmoc-N-Me-D-ThiAla-OH

[1607] Name:(2R)-2-[N-(9H-Fluoren-9-yl)methoxycarbonyl)-N-methylamino]-3-(4-fluorophenyl)propionicacid Abbreviation: Fmoc-N-Me-D-Phe(4-F)-OH

[1608] Building Block 3

[1609] Name: (2R)-2-(N-(((9H-Flouren-9-yl)methoxy)carbonyl)-N-methylamino)-3-(2-naphtyl)propionic acid

[1610] Abbreviation: Fmoc-N-Me-D-2-Nal-OH

[1611] Name:(2R)-3-(Biphenyl-4-yl)-2-(N-((9H-fluoren-9-yl)methoxycarbonyl)-N-methylamino)propionicacid

[1612] Abbreviation: Fmoc-N-Me-D-Phe(4-Phe)-OH

[1613] Building Block 4

[1614] Name: 3-(1-(tert-Butyloxycarbonylamino)ethyl)benzoic acid

[1615] Abbreviation: Boc-AEB-OH

[1616] Name: 3-(t-Butyloxycarbonylaminomethyl)benzoic acid

[1617] Abbreviation: Boc-AMB-OH

[1618] Name: (2E)-5-tert-Butoxycarbonylamino-3, 5-dimethylhex-2-enoicacid

[1619] Abbreviation: Boc-ADH-OH

[1620] Name:(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid.

[1621] Abbreviation: Boc-MAMH-OH

[1622] Name: (2S)-2-(((Carboxy)methoxy)methyl)pyrrolidin-1-carboxylicacid ten:-butyl ester

[1623] Abbreviation: Boc-SPMA-OH

[1624] Name: (2R)-2-(((Carboxy)methoxy)methyl)pyrrolidin-1-carboxylicacid tert-butyl ester

[1625] Abbreviation: Boc-RPMA-OH

[1626] Name: (2E) 5-tert-Butoxycarbonylamino-5-ethylhept-2-enoic acid

[1627] Abbreviation: Boc-AEHA-OH

[1628] Name: (2E)A4-(1-(tert-Butoxycarbonylamino)cyclobutyl)but-2-enoicacid

[1629] Abbreviation: Boc-ACBB-OH

[1630] Name: (2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoicacid

[1631] Abbreviation: Boc-AM H-OH

Example 158

[1632] The N-Me-PAL resin ([building block 1] attached to resin) (0.05mmol) with a substitution capacity of 0.6 mmol/g was repeatedly (4times) swelled in dichloromethane and dimethylformamide for 2 min andfiltered.

[1633] 1.0 Coupling:

[1634] DIEA (0.025 mmol) in DCM (0.034 ml), HATU (0.0125 mmol) in DMF(0.5 ml), a solution of HOAt (0.0125 mmol) and Fmoc-N-Me-D-Phe(4-F)-OH[building block 2] (0.0125 mmol) in DMF (0.5 ml) and DMF (0.5 ml) wereadded. The mixture was allowed to shake for 16 hours. The resin wasrepeatedly (5 times) swelled in dimethylformamide for 90 sec andfiltered.

[1635] 1.5 Coupling:

[1636] DIEA (0.00625 mmol) in DCM (0.0085 ml), HATU (0.003125 mmol) inDMF (0.125 ml), a solution of HOAt (0.003125 mmol) andFmoc-N-Me-D-Phe(4-F)-OH [building block 2] (0.003125 mmol) in DMF (1.25ml) were added. The mixture was allowed to shake for 4 hours. The resinwas repeatedly (5 times) swelled in dimethylformamide for 90 sec andfiltered.

[1637] Deprotection:

[1638] A solution of 20% piperidine in DMF (1.5 ml) was added and themixture was shaken for 20 min. The resin was repeatedly (7 times)swelled in dimethylformamide for 90 sec and filtered.

[1639] 2.0 Coupling:

[1640] DIEA (0.025 mmol) in DCM (0.034 ml), HATU (0.0125 mmol) in DMF(0.5 ml), a solution of HOAt (0.0125 mmol) and Fmoc-N-Me-D-2-Nal-OH[building block 3] (0.0125 mmol) in DMF (0.5 ml) and DMF (0.5 ml) wereadded. The mixture was allowed to shake for 16 hours. The resin wasrepeatedly (5 times) swelled in dimethylformamide for 90 sec andfiltered.

[1641] 2.5 Coupling:

[1642] DIEA (0.00625 mmol) in DCM (0.0085 ml), HATU (0.003125 mmol) inDMF (0.125 ml), a solution of HOAt (0.003125 mmol) Fmoc-N-Me-D-2-Nal-OH[building block 3] (0.003125 mmol) in DMF (1.25 ml) were added. Themixture was allowed to shake for 4 hours. The resin was repeatedly (5times) swelled in dimethylformamide for 90 sec and filtered.

[1643] Deprotection:

[1644] A solution of 20% piperidine in DMF (1.5 ml) was added and themixture was shaken for 20 min. The resin was repeatedly (7 times)swelled in dimethylformamide for 90 sec and filtered.

[1645] 3.0 Coupling:

[1646] DIEA (0.025 mmol) in DCM (0.034 ml), HATU (0.0125 mmol) in DMF(0.5 ml), a solution of HOAt (0.0125 mmol) and Boc-AMH-OH [buildingblock 4] (0.0125 mmol) in DMF (0.5 ml) and DMF (0.5 ml) were added. Themixture was allowed to shake for 16 hours. The resin was repeatedly (5times) swelled in dimethylformamide for 90 sec and filtered.

[1647] 3.5 Coupling:

[1648] DIEA (0.00625 mmol) in DCM (0.0085 ml), HATU (0.003125 mmol) inDMF (0.125 ml), a solution of HOAt (0.003125 mmol Boc-AMH-OH [buildingblock 4] (0.003125 mmol) in DMF (1.25 ml) were added. The mixture wasallowed to shake for 4 hours. The resin was repeatedly (5 times) swelledin dimethylformamide for 90 sec and filtered.

[1649] The resin was repeatedly (3 times) swelled in dichloromethane for90 sec and filtered.

[1650] The compound was cleaved off the resin and deprotected by shakingfor 10 min at −5° C. with a 50% solution of trifluoroacetic acid indichloromethane (1.5 ml). Ethanol (1.5 ml) was added and the mixture wasfiltered and concentrated in vacuo to give the desired compound.

[1651] The final product obtained was characterized by analyticalRP-HPLC (retention time) and by LC-MS (molecular mass).

[1652] The RP-HPLC analysis was performed on a Waters HPLC systemconsisting of Waters™ 600S Controller, Waters™ 996 Photodiode ArrayDetector, Waters™ 717 Autosampler, Waters™ 616 Pump, Waters™ 3 mm×150 mm3.5m C-18 Symmetry and Millennium QuickSet Control Ver. 2.15 using UVdetection at 214 nm. A gradient of 5% to 90% acetonitrile/0.1%trifluoroacetic acid/water during 15 min at 1 ml/min.

[1653] The LC-MS analysis was performed on a PE Sciex API 100 LC/MSSystem using a Water™ 3 mm×150 mm 3.5m C-18 Symmetry column and positiveionspray with a flow rate at 20 ml/min.

Examples 159-253

[1654] The following 95 compounds were synthesized in parallel asindividual entities analogously to example 158 on an Advanced ChemTechModel 384 HTS using the following ChemFile to control the operation ofthe synthesizer (Advanced ChemTech Operator's Manual, version 1.2 July1996, pp. 4-13):

[1655] ChemFile C:\ACT\CHEMFILE\2PETER.CHM Page 1

[1656] 1 Flush Arm1 with DMF and NMP, Arm2 with DCM and DMF4

[1657] 2 Empty RB1_(—)1to 96 for 3.000 minute(s)

[1658] 3

[1659] 4 Dispense System Fluid Dualarms_(—)1+4*1000 μl toRB1_(—)1to96[1-96]

[1660] 5 “Mix RB1_(—)1to96” for 2.00 minutes at 700 rpm(s)

[1661] 6 Wait for 28.000 minute(s)

[1662] 7 Empty RB1_(—)1to96 for 3.000 minute(s)

[1663] 8

[1664] 9 REM Syntesestart her. Aminosyre 1

[1665] 10 Dispense Sequence C:\ACT\displist\A1.DSP with 500 μl toRB1^(—)1to96 rack using DMF

[1666] 11 Dispense Sequence C:\ACT\displist\A2.DSP with 500 μl toRB1_(—)1to96 rack using DMF

[1667] 12 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1668] 13 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1669] 14 Transfer 68 μl from Monomer 1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1670] 15 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB1_(—)1to96[1-96]

[1671] 16 Mix “RB11to96” for 5.00 minutes at 750 rpm(s)

[1672] 17 Wait for 25.000 minute(s)

[1673] 18 Repeat from step 16, 31 times

[1674] 19 Pause

[1675] 20 Empty RB1_(—)1to96 for 3.000 minute(s)

[1676] 21 Goto ChemFile WASH_DMF.CHM, line 1

[1677] 22

[1678] 23 REM Anden kobling 1 ste AA

[1679] 24 Dispense Sequence C:\ACT\displist\A1.DSP with 125 μl toRB1_(—)1to96 rack using DMF

[1680] 25 Dispense Sequence C:\ACT\displist\A2.DSP with 125 μl toRB1_(—)1to96 rack using DMF

[1681] 26 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1682] 27 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1683] 28 Transfer 20 μl from Monomer 1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1684] 29 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB1_(—)1to96[1-96]

[1685] 30 Mix “RB1_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1686] 31 Wait for 25.000 minute(s)

[1687] 32 Repeat from step 30, 9 times

[1688] 33 Empty RB1_(—)1to96 for 3.000 minute(s)

[1689] 34 Pause

[1690] 35 Goto ChemFile COUPLING.CHM, line 1

[1691] 36 Pause

[1692] 37

[1693] 38 Goto ChemFile WASH_DMF.CHM, line 1

[1694] 39 Goto ChemFile DEPROTEC.CHM, line 1

[1695] 50 Goto ChemFile WASH_DMF.CHM, line 1

[1696] 41

[1697] 42 REM Her starter anden aminosyre-kobling

[1698] 43 Dispense Sequence C:\ACT\displist\B1.DSP with 500 μl toRB1_(—)1to96 rack using DMF

[1699] 44 Dispense Sequence C:\ACT\displist\B2.DSP with 500 μl toRB1_(—)1to96 rack using DMF

[1700] 45 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1701] 46 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1702] 47 Transfer 68 μl from Monomer 1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1703] 48 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB1_(—)1to96[1-96]

[1704] 49 Mix “RB1_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1705] 50 Wait for 25.000 minute(s)

[1706] 51 Repeat from step 49, 31 times

[1707] 52

[1708] 53 Empty RB1 1to96 for 3.000 minute(s)

[1709] 54 Goto ChemFile WASH_DMF.CHM, line 1

[1710] 55

[1711] 56 REM Anden AA. Anden kobling

[1712] 57 Dispense Sequence C:\ACT\displist\B1.DSP with 125 μl toRB1_(—)1to96 rack using DMF

[1713] 58 Dispense Sequence C:\ACT\displist\B2.DSP with 125 μl toRB1_(—)1to96 rack using DMF

[1714] 59 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1715] 60 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1716] 61 Transfer 20 μl from Monomer1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1717] 62 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB1_(—)1to96[1-96]

[1718] 63 Mix “RB1_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1719] 64 Wait for 25.000 minute(s)

[1720] 65 Repeat from step 63, 9 times

[1721] 66 Empty RB1 1to96 for 3.000 minute(s)

[1722] 67 Goto ChemFile WASH_DMF.CHM, line 1

[1723] 68 Goto ChemFile DEPROTEC.CHM, line 1

[1724] 69 Goto ChemFile WASH_DMF.CHM, line 1

[1725] 70

[1726] 71 Pause

[1727] 72

[1728] 73 REM N-terminalkobling starter her

[1729] 74 Dispense Sequence C:\ACT\displist\N1N2N3N4.DSP with 500 μl toRB1_(—)1to96 rack using DMF

[1730] 75 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1731] 76 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1732] 77 Transfer 68 μl from Monomer1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1733] 78 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB1_(—)1to96[1-96]

[1734] 79 Mix “RB1_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1735] 80 Wait for 25.000 minute(s)

[1736] 81 Repeat from step 79, 20 times

[1737] 82 Empty RB1 1to96 for 3.000 minute(s)

[1738] 83 Goto ChemFile WASH_DMF.CHM, line 1

[1739] 84

[1740] 85 REM N-terminal. Anden kobling

[1741] 86 Dispense Sequence C:\ACT\displist\N1N2N3N4.DSP with 125 μl toRB1_(—)1to96 rack using DMF

[1742] 87 Mix “RB1_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1743] 88 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB1_(—)1to96[1-96] using DMF

[1744] 89 Transfer 20 μl from Monomer1to36 [10] (DIEA) to RB1_(—)1to96[1-96] using DMF

[1745] 90 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB1_(—)1to96[1-96]

[1746] 91 Mix “RB1_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1747] 92 Wait for 25.000 minute(s)

[1748] 93 Repeat from step 91, 9 times

[1749] 94 Empty RB1 1to96 for 3.000 minute(s)

[1750] 95 Goto ChemFile WASH_DMF.CHM, line 1

[1751] 96 Goto ChemFile DEPROTEC.CHM, line 1

[1752] 97 Goto ChemFile WASH_DMF.CHM, line 1

[1753] 98

[1754] The building blocks were selected from the following groups:

[1755] [Building block 1]: N-Me-PAL, N-Phenethyl-PAL,N-(4-Pyridyl)ethyl-PAL, N-((S)-2-Hydroxypropyl)-PAL,N-(2,2-Dimethyl-3-hydroxypropyl)-PAL andN-((1-Methylpyrrolidin-2-yl)ethyl)-PAL.

[1756] [Building block 2]: Fmoc-N-Me-D-Phe(4-F)-OH andFmoc-N-Me-D-Phe(3,4-F,F)-OH.

[1757] [Building block 3]: Fmoc-N-Me-D-Nal-OH andFmoc-N-Me-D-Phe(4-Phe)-OH.

[1758] [Building block 4]: Boc-AMH-OH, Boc-ACBB-OH, Boc-SPMA-OH andBoc-AEB-OH.

[1759] See Table 1

Examples 254-353

[1760] The following 100 compounds were synthesized in parallel asindividual entities analogously to example 158 on an Advanced ChemTechModel 384 HTS using the following ChemFiles to control the operation ofthe synthesizer (Advanced ChemTech Operator's Manual, version 1.2 July1996, pp. 4-13):

[1761] ChemFile C:\ACT\CHEMFILE\3PETER.CHM Page 1

[1762] 1 Flush Arm1 with DMF and NMP, Arm2 with DCM and DMF4

[1763] 2 Empty RB2_(—)1to96 for 3.000 minute(s)

[1764] 3

[1765] 4 Dispense System Fluid Dualarms_(—)1 +4*1000 μl toRB2_(—)1to96[1-96]

[1766] 5 Mix “RB2_(—)1to96” for 2.00 minutes at 700 rpm(s)

[1767] 6 Wait for 28.000 minute(s)

[1768] 7 Empty RB2_(—)1to96 for 3.000 minute(s)

[1769] 8

[1770] 9 REM Syntesestart her. Aminosyre 1

[1771] 10 Dispense Sequence C:\ACT\displist\A1.DSP with 500 μl toRB2_(—)1to96 rack using DMF

[1772] 11 Dispense Sequence C:\ACT\displist\A2.DSP with 500 μl toRB2_(—)1to96 rack using DMF

[1773] 12 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1774] 13 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB2_(—)1to96[1-96] using DMF

[1775] 14 Transfer 68 μl from Monomer1to36 [10] (DIEA) to RB2_(—)1to96[1-96] using DMF

[1776] 15 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB2_(—)1to96[1-96]

[1777] 16 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1778] 17 Wait for 25.000 minute(s)

[1779] 18 Repeat from step 16, 31 times

[1780] 19 Pause

[1781] 20 Empty RB2_(—)1to96 for 3.000 minute(s)

[1782] 21 Goto ChemFile WASH_DMF.CHM, line 1

[1783] 23 REM Anden kobling 1ste M

[1784] 24 Dispense Sequence C:\ACT\displist\A1.DSP with 125 μl toRB2_(—)1to96 rack using DMF

[1785] 25 Dispense Sequence C:\ACT\displist\A2.DSP with 125 μl toRB2_(—)1to96 rack using DMF

[1786] 26 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1787] 27 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB2_(—)1to96[1-96] using DMF

[1788] 28 Transfer 20 μl from Monomer1to36 [10] (DIEA) to RB2 1to96[1-96] using DMF

[1789] 29 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB2_(—)1to96[1-96]

[1790] 30 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1791] 31 Wait for 25.000 minute(s)

[1792] 32 Repeat from step 30, 7 times

[1793] 33 Empty RB2_(—)1to96 for 3.000 minute(s)

[1794] 34 Goto ChemFile WASH_DMF.CHM, line 1

[1795] 35 Pause

[1796] 36

[1797] 37 Goto ChemFile DEPROTEC.CHM, line 1

[1798] 38 Goto ChemFile WASH_DMF.CHM, line 1

[1799] 40 REM Her starter anden aminosyre-kobling

[1800] 41 Dispense Sequence C:\ACT\displist\B1.DSP with 500 μl toRB2_(—)1to96 rack using DMF

[1801] 42 Dispense Sequence C:\ACT\displist\B2.DSP with 500 μl toRB2_(—)1to96 rack using DMF

[1802] 43 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1803] 44 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB2_(—)1to96[1-96] using DMF

[1804] 45 Transfer 68 μl from Monomer1to36 [10] (DIEA) to RB2_(—)1to96[1-96] using DMF

[1805] 46 Dispense System Fluid Dualarms_(—)1+4* 500 μl to RB2_(—)1to96[1-96]

[1806] 47 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1807] 48 Wait for 25.000 minute(s)

[1808] 49 Repeat from step 47, 31 times

[1809] 50

[1810] 51 Empty RB2_(—)1to96 for 3.000 minute(s)

[1811] 52 Goto ChemFile WASH_DMF.CHM, line 1

[1812] 54 REM Anden AA. Anden kobling

[1813] 55 Dispense Sequence C:\ACT\displist\B1.DSP with 125 μl toRB2_(—)1to96 rack using DMF

[1814] 56 Dispense Sequence C:\ACT\displist\B2.DSP with 125 μl toRB2_(—)1to96 rack using DMF

[1815] 57 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1816] 58 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB2_(—)1to96[1-96] using DMF

[1817] 59 Transfer 20 μl from Monomer1to36 [10] (DIEA) to RB2_(—)1to96[1-96] using DMF

[1818] 60 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB2_(—)1to96[1-96]

[1819] 61 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1820] 62 Wait for 25.000 minute(s)

[1821] 63 Repeat from step 61, 7 times

[1822] 64 Empty RB2_(—)1to96 for 3.000 minute(s)

[1823] 65 Goto ChemFile WASH_DMF.CHM, line 1

[1824] 66 Pause

[1825] 67

[1826] 68 Goto ChemFile DEPROTEC.CHM, line 1

[1827] 69 Goto ChemFile WASH_DMF.CHM, line 1

[1828] 70

[1829] 71 Pause

[1830] 72

[1831] 73 REM N-terminalkobling starter her

[1832] 74 Dispense Sequence C:\ACT\displist\N_(—)56789.DSP with 500 μlto RB2_(—)1to96 using DMF

[1833] 75 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1834] 76 Transfer 500 μl from REAGENT_(—)3[1] (HATU) toRB2_(—)1to96t[1-96] using DMF

[1835] 77 Transfer 68 μl from Monomer1to36 [10] (DIEA) to RB2_(—)1to96[1-96] using DMF

[1836] 78 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB2_(—)1to96[1-96]

[1837] 79 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1838] 80 Wait for 25.000 minute(s)

[1839] 81 Repeat from step 79, 20 times

[1840] 82 Empty RB2 1to96 for 3.000 minute(s)

[1841] 83 Goto ChemFile WASH_DMF.CHM, line 1

[1842] 84

[1843] 85 REM N-terminal. Anden kobling

[1844] 86 Dispense Sequence C:\ACT\displist\N_(—)56789.DSP with 125 μlto RB2_(—)1to96 using DMF

[1845] 87 Mix “RB2_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1846] 88 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB2_(—)1to96[1-96] using DMF

[1847] 89 Transfer 20 μl from Monomer1to36 [10] (DIEA) to RB2_(—)1to96[1-96] using DMF

[1848] 90 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB2_(—)1to96[1-96]

[1849] 91 Mix “RB2_(—)1to96” for 5.00 minutes at 750 rpm(s)

[1850] 92 Wait for 25.000 minute(s)

[1851] 93 Repeat from step 91, 7 times

[1852] 94 Empty RB2 1to96 for 3.000 minute(s)

[1853] 95 Goto ChemFile WASH_DMF.CHM, line 1

[1854] 96 Goto ChemFile WASH_DCM.CHM, line 1

[1855] 97

[1856] The building blocks were selected from the following groups:

[1857] [Building block 1]: N-Phenethyl-PAL, N-(4-Pyridyl)ethyl-PAL,N-((S)-2-Hydroxypropyl)-PAL, N-(2,2-Dimethyl-3-hydroxypropyl)-PAL andN-((1-Methylpyrrolidin-2-yl)ethyl)-PAL.

[1858] [Building block 2]: Fmoc-N-Me-D-Phe(4-F)-OH andFmoc-N-Me-D-Phe(3,4-F,F)-OH.

[1859] [Building block 3]: Fmoc-N-Me-D-Nal-OH andFmoc-N-Me-D-Phe(4-Phe)-OH.

[1860] [Building block 4]: Boc-AMB-OH, Boc-ADH-OH, Boc-MAMH-OH,Boc-RPMA-OH and Boc-AEHA-OH.

[1861] See Table 2

Examples 354-533

[1862] The following 180 compounds were synthesized in parallel asindividual entities analogously to example 158 on an Advanced ChemTechModel 384 HTS using the following ChemFiles to control the operation ofthe synthesizer (Advanced ChemTech Operator's Manual, version 1.2 July1996, pp. 4-13):

[1863] ChemFile C:\ACT\CHEMFILE\4PETER.CHM Page 1

[1864] 1 Flush Arm1 with DMF and THF, Arm2 with DCM and DMF4

[1865] 2 Empty RB3_(—)1to96 for 3.000 minute(s)

[1866] 3 Empty RB4_(—)1to96 for 3.000 minute(s)

[1867] 4

[1868] 5 Dispense System Fluid Dualarms_(—)1+4*1500 μl toRB3_(—)1to96[1-96]

[1869] 6 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1870] 7 Dispense System Fluid Dualarms_(—)1+4*1500 μl toRB4_(—)1to96[1-96]

[1871] 8 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1872] 9 Empty RB3_(—)1to96 for 3.000 minute(s)

[1873] 10 Empty RB3_(—)1to96 for 3.000 minute(s)

[1874] 11

[1875] 12 REM!! SYNTESESTART HER!!

[1876] 13

[1877] 14 REM Aminosyre 1

[1878] 15 Dispense Sequence C:\ACT\displist\A3_(—)3.DSP with 500 μl toRB3_(—)1to96 rack using DMF

[1879] 16 Dispense Sequence C:\ACT\displist\A4_(—)3.DSP with 500 μl toRB3_(—)1to96 rack using DFM

[1880] 17 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1881] 18 Dispense Sequence C:\ACT\displist\A1A2_(—)4.DSP with 500 μl toRB3_(—)1to96 rack using DMF

[1882] 19 Dispense Sequence C:\ACT\displist\A3_(—)4.DSP with 500 μl toRB4_(—)1to96 rack using DMF

[1883] 20 Dispense Sequence C:\ACT\displist\A4_(—)4.DSP with 500 μl toRB4_(—)1to96 rack using DMF

[1884] 21 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1885] 22 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB3_(—)1to96[1-96] using DMF

[1886] 23 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1887] 24 Transfer 500 μl from REAGENT_(—)3 [1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[1888] 25 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1889] 26 Dispense System Fluid Dualarms 1+4*500 μl to RB3_(—)1to96[1-96]

[1890] 27 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB4_(—)1to96[1-96]

[1891] 28 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[1892] 29 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1893] 30 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF4

[1894] 31 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1895] 32 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1896] 33 Wait for 25.000 minute(s)

[1897] 34 Repeat from step 31, 31 times

[1898] 35 Empty RB3_(—)1to96 for 3.000 minute(s)

[1899] 36 Empty RB4_(—)1to96 for 3.000 minute(s)

[1900] 37 Goto ChemFile WASH_DMF.CHM, line 1

[1901] 38

[1902] 39 REM Anden kobling 1ste AA

[1903] 40 Dispense Sequence C:\ACT\displist\A3_(—)3.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1904] 41 Dispense Sequence C:\ACT\displist\A43.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1905] 42 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1906] 43 Dispense Sequence C:\ACT\displist\A1A2_(—)4.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1907] 44 Dispense Sequence C:\ACT\Rdisplist\A3_(—)4.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1908] 45 Dispense Sequence C:\ACT\displist\A4_(—)4.DSP with 125 μl toRB4_(—)1to96 rack using DMF

[1909] 46 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1910] 47 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB3_(—)1to96[1-96] using DMF

[1911] 48 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1912] 49 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[1913] 50 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1914] 51 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB3_(—)1to96[1-96]

[1915] 52 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB4_(—)1to96[1-96]

[1916] 53 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[1917] 54 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1918] 55 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF4

[1919] 56 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1920] 57 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1921] 58 Wait for 25.000 minute(s)

[1922] 59 Repeat from step 56, 7 times

[1923] 60 Empty RB3_(—)1to96 for 3.000 minute(s)

[1924] 61 Empty RB4_(—)1to96 for 3.000 minute(s)

[1925] 62

[1926] 63 Goto ChemFile WASH_DMF.CHM, line 1

[1927] 64 Goto ChemFile DEPROTEC.CHM, line 1

[1928] 65 Goto ChemFile WASH_DMF.CHM, line 1

[1929] 66

[1930] 67 Pause

[1931] 68

[1932] 69 REM Start anden M-kobling

[1933] 70 Dispense Sequence C:\ACT\displist\B1_(—)3.DSP with 500 μl toRB3_(—)1to96 rack using DMF

[1934] 71 Dispense Sequence C:\ACT\displist\B2_(—)3.DSP with 500 μl toRB3_(—)1to96 rack using DMF

[1935] 72 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1936] 73 Dispense Sequence C:\ACT\displist\B1_(—)4.DSP with 500 μl toRB4_(—)1to96 rack using DMF

[1937] 74 Dispense Sequence C:\ACT\displist\B2_(—)4.DSP with 500 μl toRB4_(—)1to96 rack using DMF

[1938] 75 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1939] 76 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB3 1to96[1-96] using DMF

[1940] 77 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1941] 78 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[1942] 79 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1943] 80 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB3_(—)1to96[1-96]

[1944] 81 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB4_(—)1to96[1-96]

[1945] 82 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[1946] 83 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1947] 84 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF4

[1948] 85 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1949] 86 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1950] 87 Wait for 25.000 minute(s)

[1951] 88 Repeat from step 85, 31 times

[1952] 89 Empty RB3_(—)1to96 for 3.000 minute(s)

[1953] 90 Empty RB3_(—)1to96 for 3.000 minute(s)

[1954] 91 Goto ChemFile WASH_DMF.CHM, line 1

[1955] 92

[1956] 93 REM Anden kobling anden AA

[1957] 94 Dispense Sequence C:\ACT\displist\B1_(—)3.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1958] 95 Dispense Sequence C:\ACT\displiståB2_(——)3.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1959] 96 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1960] 97 Dispense Sequence C:\ACT\displist\B1_(—)4.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1961] 98 Dispense Sequence C:\ACT\displist\B2_(—)4.DSP with 125 μl toRB3_(—)1to96 rack using DMF

[1962] 99 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1963] 100 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB3_(—)1to96[1-96] using DMF

[1964] 101 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1965] 102 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[1966] 103 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1967] 104 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB3_(—)1to96[1-96]

[1968] 105 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB4_(—)1to96[1-96]

[1969] 106 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[1970] 107 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1971] 108 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF

[1972] 109 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1973] 110 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[1974] 111 Wait for 25.000 minute(s)

[1975] 112 Repeat from step 109, 7 times

[1976] 113 Empty RB3_(—)1to96 for 3.000 minute(s)

[1977] 114 Empty RB4_(—)1to96 for 3.000 minute(s)

[1978] 115

[1979] 116 Goto ChemFile WASH_DMF.CHM, line 1

[1980] 117 Goto ChemFile DEPROTEC.CHM, line 1

[1981] 118 Goto ChemFile WASH_DMF.CHM, line 1

[1982] 119

[1983] 120 Pause

[1984] 121

[1985] 122 REM N-terminal kobling start

[1986] 123 Dispense Sequence C:\ACT\displist\N_(—)3.DSP with 500 μl toRB3_(—)1to96 rack using DMF

[1987] 124 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1988] 125 Dispense Sequence C:\ACT\displist\N_(—)4.DSP with 500 μl toRB4_(—)1to96 rack using DMF

[1989] 126 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1990] 127 Transfer 500 μl from REAGENT_(—)3[1] (HATU) toRB3_(—)1to96b[1-96] using DMF

[1991] 128 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[1992] 129 Transfer 500 μl from REAGENT_(—)3[1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[1993] 130 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[1994] 131 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB3_(—)1to96[1-96]

[1995] 132 Dispense System Fluid Dualarms_(—)1+4*500 μl to RB4_(—)1to96[1-96]

[1996] 133 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[1997] 134 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[1998] 135 Transfer 68 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF4

[1999] 136 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[2000] 137 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[2001] 138 Wait for 25.000 minute(s)

[2002] 139 Repeat from step 136, 31 times

[2003] 140 Empty RB3_(—)1to96 for 3.000 minute(s)

[2004] 141 Empty RB4_(—)1to96 for 3.000 minute(s)

[2005] 142 Goto ChemFile WASH_DMF.CHM, line 1

[2006] 143

[2007] 144 REM

[2008] 145 Dispense Sequence C:\ACT\displist\N_(—)3.DSP with 125 μl toRB_(—)3_(—)1to96 rack using DMF

[2009] 146 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[2010] 147 Dispense Sequence C:\ACT\displist\N_(—)4.DSP with 125 μl toRB4_(—)1to96 rack using DMF

[2011] 148 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[2012] 149 Transfer 125 μl from REAGENT_(—)3[1] (HATU) toRB_(—)3_(—)1to96 [1-96] using DMF

[2013] 150 Mix “RB3_(—)1to96” for 30 seconds at 300 rpm(s)

[2014] 151 Transfer 125 μl from REAGENT_(—)3[1] (HATU) to RB4_(—)1to96[1-96] using DMF4

[2015] 152 Mix “RB4_(—)1to96” for 30 seconds at 300 rpm(s)

[2016] 153 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB3_(—)1to96[1-96]

[2017] 154 Dispense System Fluid Dualarms_(—)1+4*1250 μl to RB4_(—)1to96[1-96]

[2018] 155 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB3_(—)1to96[1-96] using DMF

[2019] 156 Mix “RB3_(—)1to96” for 1.00 minutes at 600 rpm(s)

[2020] 157 Transfer 20 μl from Monomer1to36 [16] (DIEA) to RB4_(—)1to96[1-96] using DMF4

[2021] 158 Start mixing “RB3_(—)1to96” for 5.00 minutes at 600 rpm(s)

[2022] 159 Mix “RB4_(—)1to96” for 5.00 minutes at 600 rpm(s)

[2023] 160 Wait for 25.000 minute(s)

[2024] 161 Repeat from step 158, 7 times

[2025] 162 Empty RB3_(—)1to96 for 3.000 minute(s)

[2026] 163 Empty RB4_(—)1to96 for 3.000 minute(s)

[2027] 164 Goto ChemFile WASH_DMF.CHM, line 1

[2028] 165

[2029] The building blocks were selected from the following groups:

[2030] [Building block 1]: N-Phenethyl-PAL, N-(4-Pyridyl)ethyl-PAL,N-((S)-2-Hydroxypropyl)-PAL, N-(2,2-Dimethyl-3-hydroxypropyl)-PAL andN-((1-Methylpyrrolidin-2-yl)ethyl)-PAL.

[2031] [Building block 2]: Fmoc-N-Me-D-Phe-OH and Fmoc-N-Me-D-ThiAla-OH.

[2032] [Building block 3]: Fmoc-N-Me-D-Nal-OH andFmoc-N-Me-D-Phe(4-Phe)-OH.

[2033] [Building block 4]: Boc-AMH-OH, Boc-ACBMA-OH, Boc-RPMA-OH,Boc-AEB-OH, Boc-AMB-OH, Boc-ADH-OH, Boc-MAMH-OH, Boc-RPMA-OH andBoc-AEHA-OH.

[2034] See Table 3 TABLE 1 Example Structure MW HPLC LCMS 158

546.7 9.91 546.8 159

568.7 9.68 569.0 160

562.7 9.38 563.0 161

558.7 9.63 559.0 162

572.7 10.11 573.0 163

594.7 164

588.7 10.02 589.2 165

584.7 166

564.7 9.68 565.0 167

586.7 9.83 587.2 168

580.7 9.61 581.0 169

576.7 576.8 170

590.7 171

612.7 10.49 613.2 172

606.7 10.26 607.0 173

602.7 10.50 603.0 174

636.8 10.73 637.2 175

658.8 10.97 659.2 176

652.8 11.07 653.2 177

648.8 178

662.9 11.56 663.2 179

684.9 11.81 685.0 180

678.9 11.60 679.0 181

674.9 11.95 675.2 182

654.8 11.28 655.0 183

676.8 11.40 677.2 184

670.8 11.27 672.2 185

666.8 11.44 667.2 186

680.8 11.80 681.0 187

702.9 12.10 702.8 188

696.8 11.97 697.0 189

692.9 190

637.8 8.06 638.2 191

659.8 8.27 660.0 192

653.8 8.05 654.2 193

649.8 8.33 650.2 194

663.8 8.44 664.2 195

685.8 8.84 686.0 196

679.8 8.61 680.0 197

675.9 198

655.8 8.37 656.0 199

677.8 8.45 678.0 200

671.8 8.26 672.2 201

667.8 8.51 668.0 202

681.8 8.52 682.0 203

703.8 8.63 704.0 204

697.8 8.79 689.2 205

693.8 8.99 206

643.9 7.95 644.2 207

665.9 8.08 666.2 208

659.9 8.15 660.0 209

655.9 8.35 656.2 210

669.9 8.77 670.2 211

691.9 8.93 692.2 212

685.9 8.70 686.0 213

681.9 214

661.8 7.88 662.2 215

683.8 8.53 684.0 216

677.8 8.36 678.0 217

673.9 218

687.9 219

709.9 9.11 710.0 220

703.9 8.91 705.0 221

699.9 222

618.8 9.18 619.0 223

640.8 224

634.8 9.42 635.2 225

630.8 9.98 629.8 226

644.8 227

666.8 10.78 667.4 228

660.8 229

656.8 230

636.8 231

658.8 9.90 658.0 232

652.8 9.66 653.0 233

648.8 234

662.8 10.34 663.0 235

684.8 236

678.8 10.01 679.2 237

674.8 238

590.7 8.48 591.0 239

612.8 9.52 613.0 240

606.7 9.28 607.0 241

602.8 9.59 603.0 242

616.8 9.05 617.2 243

638.8 8.97 639.0 244

632.8 633.0 245

628.8 629.0 246

608.7 9.12 608.8 247

630.7 9.72 631.0 248

624.7 9.51 625.0 249

620.7 9.26 621.0 250

634.8 251

656.8 9.50 656.8 252

650.8 9.50 651.0 253

646.8 9.48

[2035] TABLE 2 Example Structure MW HPLC LC-MS 254

651.83 255

645.78 256

653.80 257

651.83 258

665.86 259

677.87 260

671.82 261

679.84 262

677.87 263

691.90 264

669.82 265

663.77 266

671.79 267

669.82 268

683.85 269

695.86 270

689.81 271

697.83 272

695.86 273

709.89 274

650.84 275

644.80 276

652.82 277

650.84 278

664.87 279

676.88 280

670.83 281

678.85 282

676.88 283

690.91 284

668.83 285

662.79 286

670.81 287

668.83 288

682.86 289

694.87 290

688.82 291

696.84 292

694.87 293

708.90 294

657.88 295

651.83 296

659.85 297

657.88 298

671.91 299

683.92 300

677.87 301

685.89 302

683.92 303

697.94 304

675.87 305

669.82 306

677.84 307

675.87 308

689.90 309

701.91 310

695.86 311

703.88 312

701.91 313

715.94 314

604.77 315

598.72 316

606.74 317

604.77 318

618.80 319

630.81 320

624.76 321

632.78 322

630.81 323

644.84 324

622.76 325

616.71 326

624.73 327

622.76 328

636.79 329

648.80 330

642.75 331

650.77 332

648.80 333

662.83 334

632.83 335

626.78 336

634.80 337

632.83 338

646.85 339

658.86 340

652.82 341

660.84 342

658.86 343

672.89 344

650.82 345

644.77 346

652.79 347

650.82 348

664.84 349

676.85 350

670.81 351

678.83 352

676.85 353

690.88

[2036] TABLE 3 Example Structure MW HPLC LC-MS 354

624.9 355

646.9 356

640.9 357

636.9 358

638.9 359

632.8 360

640.9 361

638.9 362

652.9 363

650.9 364

672.9 365

666.9 366

662.9 367

664.9 368

658.9 369

666.9 370

664.9 371

678.9 372

618.8 373

640.8 374

634.8 375

630.8 376

632.9 377

626.8 378

634.8 379

632.9 380

646.9 381

644.9 382

666.9 383

660.9 384

656.9 385

658.9 386

652.8 387

660.9 388

658.9 389

672.9 390

625.8 391

647.8 392

641.8 393

637.9 394

639.9 395

633.8 396

641.8 397

639.9 398

653.9 399

651.9 400

673.9 401

667.9 402

663.9 403

665.9 404

659.9 405

667.9 406

665.9 407

679.9 408

619.8 409

641.8 410

635.8 411

631.8 412

633.8 413

627.8 414

635.8 415

633.8 416

647.9 417

645.9 418

667.9 419

661.9 420

657.9 421

659.9 422

653.8 423

661.9 424

659.9 425

673.9 426

631.9 427

653.9 428

647.9 429

643.9 430

645.9 431

639.9 432

647.9 433

645.9 434

659.9 435

657.9 436

679.9 437

673.9 438

669.9 439

672.0 440

665.9 441

673.9 442

672.0 443

686.0 444

625.9 445

647.9 446

641.9 447

637.9 448

639.9 449

633.8 450

641.9 451

639.9 452

653.9 453

651.9 454

673.9 455

667.9 456

663.9 457

665.9 458

659.9 459

667.9 460

665.9 461

680.0 462

606.8 463

628.8 464

622.8 465

618.8 466

620.9 467

614.8 468

622.8 469

620.9 470

634.9 471

632.9 472

654.9 473

648.9 474

644.9 475

646.9 476

640.9 477

648.9 478

646.9 479

660.9 480

600.8 481

622.8 482

616.8 483

612.8 484

614.8 485

608.8 486

616.8 487

614.8 488

628.9 489

626.8 490

648.9 491

642.8 492

638.9 493

640.9 494

634.8 495

642.8 496

640.9 497

654.9 498

578.8 499

600.8 500

594.8 501

590.8 502

592.8 503

586.8 504

594.8 505

592.8 506

606.8 507

604.8 508

626.8 509

620.8 510

616.8 511

618.8 512

612.8 513

620.8 514

618.8 515

632.9 516

572.8 517

594.8 518

588.8 519

584.8 520

586.8 521

580.7 522

588.8 523

586.8 524

600.8 525

598.8 526

620.8 527

614.8 528

610.8 529

612.8 530

606.8 531

614.8 532

612.8 533

626.8

Example 534

[2037] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(N-methyl-N-(3-dimethylaminopropyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[2038] The title compound was prepared as in example 1 usingN,N,N′-trimethylpropylenediamine instead of methylamine.

Example 535

[2039] (2E)-5-Amino-5-methylhex-2-enoic AcidN-((1R)-1-(N-((1R)-1-(N-methylcarbamoyl)-2-phenylethyl)-N-ethylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[2040] The title compound was prepared as in example 1. N-ethylation ofD-Boc-phenylalanine was carried out by the use of ethyl iodide insteadof methyl iodide.

Example 536

[2041] (2E)-5-Amino-5-methylhex-2-enoicAcid-N-(1R)-1-(N-((1R)-1-(N-(N,N-dimethylcarbamoylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[2042] The title compound was prepared as in example 1 using glycinedimethylamide instead of methylamine.

Example 537

[2043] (2E)-5-Amino-5-methylhex-2-enoicAcid-N-((1R)-1-(N-((1R)-1-(N-(carbamoylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide

[2044] The title compound was prepared as in example 1 using glycineamide instead of methylamine.

1. A compound of general formula I

wherein R¹ and R² are independently hydrogen, or C₁₋₆-alkyl optionallysubstituted with aryl; a and b are independently 1 or 2; G is hydrogen,—O—(CH₂)_(k)—R²⁷,

wherein R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵ and R³⁶independently are hydrogen, halogen, aryl, C₁₋₆-alkyl or C₁₋₆-alkoxy; kand l are independently 0, 1 or 2; D is

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸and R⁹ are independently hydrogen orC₁₋₆-alkyl optionally substituted with halogen, amino, hydroxyl or aryl;n, m and q are independently 0 1, 2, or 3; p is 0 or 1; M is—CR¹¹═CR^(11a)—, aryl, —O—, or —S—; R¹¹ and R^(11a) are independentlyhydrogen, or C₁₋₆-alkyl optionally substituted with aryl; with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is different fromhydrogen, when E is —CONR¹²R¹³, —(CH₂)_(v)—NR¹²SO₂R¹⁴,—(CH₂)_(v)—NR¹²COR¹³, —(CH₂)_(v)-OR^(13a), —CH₂)_(v)—OCOR¹³,—CH(R¹²)R¹³, —(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴, —(CH₂)_(v)—NR¹²—CO—NR¹³R¹⁴,

wherein X is —N(R¹⁵)—, —O— or —S—, V is —C(R¹⁶)═ or —N═, Y is —C(R¹⁷)═or —N═, Z is —C(R¹⁸)═ or —N═, R¹⁵ is hydrogen or C₁₋₆-alkyl optionallysubstituted with aryl, R¹⁶, R¹⁷ and R¹⁸ independently are hydrogen,—COOR¹⁹, —CONR²⁰R²¹, —(CH)_(w)NR²⁰R²¹, —(CH₂)_(w)OR¹⁹, —(CH₂)_(w)R¹⁹ orhalogen; R¹², R¹³, R¹⁹, R²⁰ and R²¹ independently are hydrogen orC₁₋₆-,alkyl optionally substituted with halogen, —N(R²²)R²³, —CF₃,hydroxyl, C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy oraryl, or R¹³ is

wherein Q is —CH< or —N<, K and L are independently —CH₂—, —CO—, —O—,—S—, —NR²⁶— or a valence bond, where R²⁶ is hydrogen or C₁₋₆-alkyl; tand u are independently 0, 1, 2, 3 or 4; R^(13a) is C₁₋₆ alkylsubstituted with aryl; R¹⁴ is C₁₋₆ alkyl; R²² and R²³ are independentlyhydrogen or C₁₋₆-alkyl; v and w are independently 0, 1, 2 or 3; or D isR⁷—NH—(CR⁸R⁹)_(p)—(CH₂)_(m)—M—(CHR¹⁰)_(o)—(CH₂)_(n)— wherein R⁷, R⁸,R⁹and R¹⁰ are independently hydrogen or C₁₋₆ alkyl optionallysubstituted with halogen, amino, hydroxyl or aryl; R⁷, and R⁸ or R⁷, andR⁹ or R⁸ and R⁹ optionally forming —(CH₂)_(i)—U—(CH₂)_(j)—, wherein iand j are independently are 1 or 2 and U is —O—, —S— or a valence bond;n and m are independently 0, 1, 2, or 3; o and p are independently 0 or1; M is —CR¹¹═CR^(11a)—, aryl, —O—, or —S—; R¹¹ and R^(11a) areindependently hydrogen, or C₁₋₆-alkyl optionally substituted with aryl,when E is —CONR¹²R¹³, —(CH₂)_(v)—NR¹²SO₂R¹⁴, —(CH₂)_(v)—NR¹²COR¹³,—(CH₂)_(v)—OR^(13a), —CH₂)_(v)—OCOR¹³, —CH(R¹²)R¹³,—(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴ or —(CH₂)_(v)—NR¹²—CO—NR¹³R¹⁴, wherein R¹²and R¹³ independently are hydrogen or C₁₋₆-alkyl optionally substitutedwith halogen, —CONR²²R²³, —N(R²²)R²³, —CF₃, hydroxyl, C₁₋₆-alkoxy,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl; or R¹³ is

wherein Q is —CH< or —N<, K and L are independently —CH₂—, —CO—, —O—,—S—, —NR²⁶— or a valence bond, where R²⁶ is hydrogen or C₁₋₆ alkyl; tand u are independently 0, 1, 2, 3 or 4; R^(13a) is C₁₋₆ alkylsubstituted with aryl; R¹⁴ is C₁₋₆ alkyl; R²² and R²³ are independentlyhydrogen or C₁₋₆ alkyl; v and w are independently 0, 1, 2 or 3; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein D is

wherein R³, R⁴, R⁵, R⁶, R⁸ and R⁹are independently hydrogen or methyl;n, m and q are independently 0, 1 or 2; M is —CR¹¹═CR^(11a)—, aryl or—O—; R¹¹ and R^(11a) are independently hydrogen, or C₁₋₆-alkyloptionally substituted with aryl, with the proviso that at least one ofR³, R⁴, R⁵ and R⁶ is different from hydrogen, when E is —CONR¹²R¹³,—(CH₂)_(v)—NR¹²SO₂R¹⁴, —(CH₂)_(v)—NR¹²COR¹³, —(CH₂)_(v)—OR^(13a),—CH₂)_(v)—OCOR¹³, —CH(R¹²)R¹³, —(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴,—(CH₂)_(v)—NR¹²—CO—NR¹³R¹⁴,

X is —N(R¹⁵)—, —O— or —S—, V is —C(R¹⁶)═ or —N═, Y is —C(R¹⁷)═ or —N═, Zis —C(R¹⁸)═ or —N═, R¹⁵ is hydrogen or C₁₋₆-alkyl optionally substitutedwith aryl, R¹⁶, R¹⁷ and R¹⁸ independently are hydrogen, —COOR¹⁹,—CONR²⁰R²¹, —(CH₂)_(w)NR²⁰R²¹, —(CH₂)_(w)OR¹⁹, —(CH₂)_(w)R¹⁹ or halogen;R¹², R¹³, R¹⁹, R²⁰and R²¹ independently are hydrogen or C₁₋₆-alkyloptionally substituted with halogen, —N(R²²)R²³, —CF₃, hydroxyl,C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl, or R¹³is

wherein Q is—CH< or —N<, K and L are independently —CH₂—, —CO—, —O—,—S—, —NR²⁶— or a valence bond, where R²⁶ is hydrogen or C₁₋₆-alkyl; tand u are independently 0, 1, 2, 3 or 4; R^(13a) is C₁₋₆ alkylsubstituted with aryl; R¹⁴ is C₁₋₆ alkyl; R²² and R²³ are independentlyhydrogen or C₁₋₆-alkyl; and v and w are independently 0, 1, 2 or
 3. 3. Acompound according to claim 1 wherein D isR⁷—NH—(CR⁸R⁹)_(p)—(CH₂)_(m)—M—(CHR¹⁰)_(o)(CH₂)_(n)—wherein R⁸ and R⁹ areindependently hydrogen or methyl; R⁷ and R¹⁰ are independently hydrogenor C₁₋₆ alkyl optionally substituted by halogen, amino, hydroxyl oraryl; or R⁷and R⁸ or R⁸ and R⁹ can form —(CH₂)_(i)—U—(CH₂)_(j)—, whereini and j independently are 1 or 2 and U is —O—, —S— or a valence bond; nand m are independently 0, 1, or 2; M is —CR¹¹═CR^(11a)—, aryl or —O—;R¹¹ and R^(11a) are independently hydrogen, or C₁₋₆-alkyl optionallysubstituted with aryl, when E is —CONR¹²R¹³, —CH₂)_(v)—NR¹²SO₂R¹⁴,—(CH₂)_(v)—NR¹²COR¹³, —(CH₂)_(v)—OR^(13a), —CH₂)_(v)—OCOR¹³,—CH(R¹²)R¹³, —(CH₂)_(v)—NR¹²—CS—NR¹³R¹⁴ or —(CH₂)_(v)—NR¹²—CO—NR¹³R¹⁴,wherein R¹² and R¹³ independently are hydrogen or C₁₋₆-alkyl optionallysubstituted with halogen, —CONR²²R²³, —N(R²²)R²³, —CF₃, hydroxyl,C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyloxy or aryl; or R¹³is

wherein Q is —CH< or —N<, K and L are independently —CH₂—, —CO—, —O—,—S—, —NR²⁶— or a valence bond, where R²⁶ is hydrogen or C₁₋₆ alkyl; tand u are independently 0, 1, 2, 3 or 4; R^(13a) is C₁₋₆ alkylsubstituted with aryl; R¹⁴ is C₁₋₆ alkyl; R²² and R²³ are independentlyhydrogen or C₁₋₆ alkyl; v and w are independently 0, 1, 2 or
 3. 4. Acompound according to claim 1, 2 or 3 wherein D is3-(1-aminoethyl)phenyl, 4-amino-4-ethylhex-1-enyl,(1E)-2-(azetidin-3-yl)ethenyl, piperidin-4-ylidenyl,2-methylpiperidin-4-yl, 2-methylpiperidin-3-yl, 2-methylpiperidin-5-yl,(1,2,3,4-tetrahydroisoquinolin-1-yl)methyl, 4-aminocyclohexyl,2-piperidylmethoxymethyl, 4-piperidyloxymethyl,2-(2-amino-2-methylpropyl)cyclopropyl,(((2R)-pyrrolidin-2-yl)methoxy)methyl,(1E)-4-amino-1-benzyl-4-methylpent-1-enyl,(1E)-4-amino-4-methylpent-1-enyl, (2-amino-2-methylpropoxy)methyl,(2S)-(2-pyrrolidinyl)methoxymethyl, (2R)-(2-pyrrolidinyl)methoxymethyl,(1E)-4-amino-2,4-dimethylpent-1-enyl,(1E)-4-methyl-4-(methylamino)pent-1-enyl, (1Z)-4-amino-4-methylpent-1-enyl,(1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl,(2-aminobutoxy)methyl, 3-(1-aminoethyl)phenyl, 3-aminomethylphenyl,3-(1-amino-1-methylethyl)phenyl, 2-(1-aminocyclopropyl)ethenyl,3-(1-aminocyclobutyl)-1-propenyl, 3-(1-aminocyclopropyl)-1-propenyl or2-(1-amino cyclobutyl)ethenyl.
 5. A compound according to claim 1, 2 or3 wherein E is methylcarbamoyl, ethylcarbamoyl, N,N-dimethylcarbamoyl,2-methoxyethylcarbamoyl, (2S)-2-hydroxypropylcarbamoyl,(2R)-2-hydroxypropylcarbamoyl, (cyclopropylmethyl)carbamoyl,(2-(acetoxy)-2-methylpropyl)carbamoyl, phenylethylcarbamoyl,4-pyridylcarbamoyl, (3-acetoxypropyl)carbamoyl,(3-hydroxypropyl)carbamoyl, methylsulfonylaminomethyl,((tetrahydrofuran-2-yl)methyl)carbamoyl, 3-cyclopropylthioureido,N-methyl-N-(methylsulfonylamino)methyl, (2,2,2-trifluoroethyl)carbamoyl,cyclopropylcarbamoyl, ((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl,3-methyl-1,2,4-oxadiazol-5-yl, methylsulfonylaminomethyl,2,2-dimethyl-3-hydroxypropylcarbamoyl,2-(1-methylpyrrolidine-2-yl)ethylcarbamoyl,N-methyl-N-(3-(dimethylamino)propyl)carbamoyl,N-(N,N-dimethylcarbamoyl)-N-methylcarbamoyl,N-(carbamoylmethyl)carbamoyl or 3-cyclopropylthioureido.
 6. The compoundaccording to any one of claims 1-5 wherein R¹ and R² independently arehydrogen, methyl or ethyl.
 7. The compound according to any one of theclaims 1-6 wherein a and b independently are
 1. 8. A compound accordingto any one of the claims 1-7 wherein G is hydrogen, —O—(CH₂)_(k)—R²⁷,

wherein R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵ and R³⁶independently are hydrogen, halogen, aryl, C₁₋₆-alkyl or C₁₋₆-alkoxy;and k and l are
 1. 9. A compound according to any one of the claims 1-8wherein R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, and R³⁶ arehydrogen, halogen, or phenyl.
 10. A compound according to claim 1, 2, 3,4, 5, 6, 7, 8 or 9 selected from the group consisting of(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,or the hydrochloride salt, (2E)-3-(3-Azetidinyl)acrylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-(Piperidin-4-ylidene)acetic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-(2-Amino-2-methylpropyl)cyclopropanecarboxylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-(2-Amino-2-methylpropoxy)acetic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-Methylpiperidine-4-carboxylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-Methylpiperidine-3-carboxylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-Methylpiperidine-5-carboxylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amid e, 2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,4-Aminocyclohexanecarboxylic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(benzylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(phenethylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-{N-[(1R)-1-(acetylamino-methyl)-2-phenyiethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-methyl-N-[(1R)-1-(methylsulfonylaminomethyl)-2-phenylethyl]carbamoyl}-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-((cyclopropyl-methyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(N-(2-methoxy-ethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((N-tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(N-2-hydroxy-propylcarbamoyl)-2-phenylethyl)N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(N-(3-(2-oxopyrrolidin-1-yl)propyl)carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-{N-[(1R)-1-((2,5-dioxopyrrolidine-1-yl)methyl)-2-phenylethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methyl-amino)-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-yl)methyl)carbamoyl)-ethyl)propionamide,(2E)-5-Amino-3,5-dimethylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((2-tetrahydrofuranyl)methyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)-N-methylamide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-((1R)-1-(cyclopropylmethyl)carbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)-propionamide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)methylamino)-N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)N-methylamino)-N-((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-3-(2-naphthyl)propionamide,(2E)-5-Amino-5-methylhex-2-enoic acid((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide,(2E)-5-Amino-3,5-dimethylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,2-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethylacetate, (2E)-5-Amino-2-benzyl-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(1-naphthyl)ethyl)amide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl)propionamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-2-(benzo[b]thiophen-3-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)N-methylamide,(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methyl-amino)-3-(benzo-[b]thiophen-3-yl)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)-methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)amide,3-((2R)-2-(N-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propylacetate, or the hydrochloride salt, (2E)-5-Amino-5-methylhex-2-enoicacid N-((1R)-1-(N-((1R)-1-(3-hydroxy-propylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,or the acetate salt, (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)methyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,or the hydrochloride salt,N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-{[(2-piperidinyl)methoxy]acetyl}amino)-3-(2-naphthyl)propionamide,4-Aminocyclohexanecarboxylic acidN-methyl-N-((1R)-1-[N-methyl-N-{(1R)-1-(methylcarbamoyl)-2-phenylethyl}carbamoyl]-2-(2-naphtyl)ethyl)amide,or the acetate salt,(2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-[{piperidin-4-yloxy}acetyl]amino)-3-(2-naphthyl)propionamide,2-Methyl-piperidine-4-carboxylic acidN-{1-[N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2-naphthyl)ethyl}amide,or the acetate salt;(2R)-2-(N-((2R)-2-(N-((2E)-5-((2R)-2-Hydroxypropylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-N-methyl-3-phenylpropionamide;(2E)-5-Amino-N-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-5-methyl-N-methylhex-2-enamide;3-(1-Aminoethyl)benzoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,5-Amino-5-methyl-hex-2-enoic acid ((1R)-1-(((1R)-1-((2R)-2-hydroxypropylcarbamoyl)-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide, (4-(1-Aminocyclobutyl)but-2-enoic acid((1R)-1-(((1R)-1-(1-methylcarbamoyl-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide,5-Amino-5-methyl-hex-2-enoic acid ((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(2-thienyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide,(2R)-2-(N-[(2R)-2-(N-[(2-Aminobutoxy)acetyl]-N-methylamino)-3(2-naphthyl)propionyl]-N-methylamino)-N-methyl-3-phenylpropionamide,(2R)-N-Methyl-2-(N-methyl-N-((2R)-2-(N-methyl-N-((((2S)-pyrrolidin-2-yl)methoxy)acetyl)amino)-3-(2-naphthyl)propionyl)amino)-3-phenylpropionamide,3-((2R)-2-(N-((2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate, (2E)-5-Amino-5-methylhex-2-enoicacidN-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2R)-N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N-[{piperidin-4-yloxy}acetyl]amino)-3-(2-naphthyl)propionamide,N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-2-(N-methyl-N{[(2-piperidinyl)methoxy]acetyl}amino)-3-(2-naphthyl)propinamide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamnoyl}-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}2-(4-methoxyphenyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(1-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(1-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(2-naphthyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenyl)ethyl)amide, (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-(1-naphthyl)ethyl)amide,(2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-{N-[(1R)-2-phenyl-1-(methylcarbamoyl)ethyl]-N-methylcarbamoyl}-2-phenylethyl)amide,1-((2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl-2-benzyl-4-ethylsemi-carbazide,1-((2S)-2-(N-(2-(((2R)-pyrrolidin-2-yl)methoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl-2-benzyl-4-ethylsemicarbazide,1-((2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-2-benzyl-4-ethylsemicarbazide,(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Methyl-5-methylaminohex-2enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2E)-5-Amino-3,5-dimethylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl) amide, (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-(2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)carbamoyl)-2-(1-naphthyl)ethyl)amide, 5-Amino-3,5-dimethylhex-2-enoic acidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide, (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide,(2E)-5-Methyl-5-methylaminohex-2-enoic acidN-((1R)-1-(N-((1R)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide, (2E)5-Methyl-5-amino-5-methylhex-2-enoicacid-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thien-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide, 5-methylamino-hex-2-enoic acid((1R)-1-(((1R)-2-(3,4-difluorophenyl)-1-methylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide, 5-methylamino-hex-2-enoic acid((1R)-1-(((1R) -2-phenyl-1-ethylcarbamoylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide, 5-Amino-5-methyl-hex-2-enoic acid((1R)-1-(((1R)-1-((2S)-2-hydroxypropylcarbamoyl)-2-(3,4-difluorophenyl)ethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylamide,5-Amino-5-methyl-hex-2-enoic acid(1-{[2-(2-fluorophenyl)-1-methylcarbamoylethyllmethy]carbamoyl}-2-(2-naphthyl)ethyl)methylamide,(2Z)-5-Amino-3,5-dimethylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide,(2R)-2-(N-((2E)-5-Amino-5-methylhex-2-enoyl)-N-methylamino)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-3-(2-naphthyl)propionamide,(2R)-2-(N-[{2-Amino-2-methylpropoxy}acetyl]-N-methylamino)-N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)propionamide,(2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide,and its acetate salt; (2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;(2E)-4-(1-Aminocyclobutyl)but-2-enoic acidN-((1R)-1-(N-((1R)-2-(3,4-difluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;(2E)-4-(1-Aminocyclobutyl)but-2-enoic acidN-((1R)-1-(N-((1R)-1-(cyclopropylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;(2E) 4-(1-Aminocyclobutyl)-but-2-enoic acidN-((1R)-2-(biphenyl-4-yl)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;3-(1-Aminomethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-2-(methylcarbamoyl)-2-(2thienyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(benzyloxy)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N(1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(benzyloxy)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(2-naphthyl)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(benzyloxy)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(2-fluorophenyl)ethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-1oN-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propion-amide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(benzyloxy)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(biphenyl-4-yl)propionamide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(2-naphthyl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)-propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(2-naphthyl)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(2-naphthyl)-ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)-benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzo[b]thiophen-3-yl)propionamide; (2E)-5-Amino-5-methylhex-2-enoic acidN-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzo[b]thiophen-3-yl)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(benzyloxy)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;(2R)-2-(N-((2-Amino-2-methylpropoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(benzyloxy)propionamide;(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)carbamoyl)-2-(benzyloxy)ethyl)amide;3-(1-Aminoethyl)-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)-ethyl)carbamoyl)-2-(biphen-4-yl)ethyl)benzamide;3-Aminomethyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-carbamoyl)-2-(biphenyl-4-yl)ethyl)benzamide;(2R)-2-(N-((2-Aminobutoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2R)-2-(N-((((2S)-2-Pyrrolidinyl)methoxy)acetyl)-N-methylamino)-N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(4-methoxyphenyl)ethyl)-3-(biphenyl-4-yl)propionamide;(2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide;(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(N-methyl-N-(3-dimethylaminopropyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;(2E)-5-Amino-5-methylhex-2-enoic acidN-((1R)-1-(N-((1R)-1-(N-methylcarbamoyl)-2-phenylethyl)-N-ethylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;(2E)-5-Amino-5-methylhex-2-enoic acid-N-((1R)-1-(N-((1R)-1-(N-(N,N-dimethylcarbamoylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;or (2E)-5-Amino-5-methylhex-2-enoicacid-N-((1R)-1-(N-((1R)-1-(N-(carbamoylmethyl)carbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylamide;or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 selected from the group consistingof


12. A pharmaceutical composition comprising, as an active ingredient, acompound according to any one of the preceeding compound claims or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.
 13. A compositionaccording to claim 12 in unit dosage form, comprising from about 10 toabout 200 mg of the compound according to any one of the preceedingcompound claims or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition for stimulating the release of growth hormonefrom the pituitary, the composition comprising, as an active ingredient,a compound according to any one of the preceeding compound claims or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.
 15. A pharmaceuticalcomposition according to any one of the claims 12-14 for oral, nasal,transdermal, pulmonal, or parenteral administration.
 16. A method ofstimulating the release of growth hormone from the pituitary, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound according to any one of the preceeding compoundclaims or a pharmaceutically acceptable salt thereof, or of acomposition according to any one of the preceeding composition claims.17. A method of increasing the rate and extent of growth, the milk andwool production, or for the treatment of ailments, the method comprisingadministering to a subject in need thereof an effective amount of acompound according to any one of the preceeding compound claims or apharmaceutically acceptable salt thereof, or of a composition accordingto any one of the preceeding composition claims.
 18. The methodaccording to claim 16 or 17, wherein the effective amount of thecompound according to any one of the preceeding compound claims or apharmaceutically acceptable salt or ester thereof is in the range offrom about 0.0001 to about 100 mg/kg body weight per day, preferablyfrom about 0.001 to about 50 mg/kg body weight per day.
 19. The methodaccording to any one of the claims 16-18, wherein said administration iscarried out by the oral, nasal, transdermal, pulmonal, or parenteralrute.
 20. Use of a compound according to any one of the preceedingcompound claims or a pharmaceutically acceptable salt thereof for thepreparation of a medicament.
 21. Use of a compound according to any oneof the preceeding compound claims or a pharmaceutically acceptable saltthereof for the preparation of a medicament for stimulating the releaseof growth hormone from the pituitary.
 22. Use of a compound according toany one of the preceeding compound claims or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament foradministration to animals to increase their rate and extent of growth,to increase their milk and wool production, or for the treatment ofailments.
 23. Use of a compound according to any one of the preceedingcompound claims or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment of stimulation of growthhormone release in the elderly; prevention of catabolic side effects ofglucocorticoids, prevention and treatment of osteoporosis, stimulationof the immune system, acceleration of wound healing, accelerating bonefracture repair, treatment of growth retardation, treating renal failureor insufficiency resulting from growth retardation, treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness, treatment of obesityand growth retardation associated with obesity, treating growthretardation associated with the Prader-Willi syndrome and Tumer'ssyndrome; accelerating the recovery and reducing hospitalization of burnpatients; treatment of intrauterine growth retardation, skeletaldysplasia, hypercortisolism and Cushing's syndrome; induction ofpulsatile growth hormone release; replacement of growth hormone instressed patients, treatment of osteochondrodysplasias, Noonan'ssyndrome, schizophrenia, depressions, Alzheimer's disease, delayed woundhealing and psychosocial deprivation, treatment of pulmonary dysfunctionand ventilator dependency, attenuation of protein catabolic responsesafter major surgery, reducing cachexia and protein loss due to chronicillness such as cancer or AIDS; treatment of hyperinsulinemia includingnesidioblastosis, adjuvant treatment for ovulation induction; tostimulate thymic development and prevent the age-related decline ofthymic function, treatment of immunosuppressed patients, improvement inmuscle strength, mobility, maintenance of skin thickness, metabolichomeostasis, renal homeostasis in the frail elderly, stimulation ofosteoblasts, bone remodelling and cartilage growth, stimulation of theimmune system in companion animals and treatment of disorder of aging incompanion animals, growth promoter in livestock and stimulation of woolgrowth in sheep.